Indazole-3-carboxamides and their use as Wnt/β-catenin signaling pathway inhibitors

ABSTRACT

Indazole-3-carboxamide compounds for treating various diseases and pathologies are disclosed. More particularly, the present invention concerns the use of an indazole-3-carboxamide compound or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., cancer, abnormal cellular proliferation, angiogenesis and osteoarthritis), the modulation of cellular events mediated by Wnt pathway signaling, as well as genetic diseases and neurological conditions/disorders/diseases due to mutations or dysregulation of the Wnt pathway and/or of one or more of Wnt signaling components. Also provided are methods for treating Wnt-related disease states.

RELATED APPLICATIONS Cross-Reference to Related Applications

This application is a continuation application of U.S. application Ser.No. 16/576,308, filed on Sep. 19, 2019, which is a continuationapplication of U.S. application Ser. No. 15/709,057, now U.S. Pat. No.10,464,924, filed Sep. 19, 2017, which is a continuation application ofU.S. application Ser. No. 14/940,958, now U.S. Pat. No. 9,802,916, filedNov. 13, 2015, which is a continuation of U.S. application Ser. No.13/614,296, now U.S. Pat. No. 9,221,793, filed Sep. 13, 2012, whichclaims the benefit of U.S. Provisional Application No. 61/534,601, filedSep. 14, 2011, and U.S. Provisional Application No. 61/624,646, filedApr. 16, 2012, which are incorporated herein by reference in theirentirety.

BACKGROUND OF THE INVENTION Field of the Invention

This invention relates to the field of therapeutic oncology. Moreparticularly, it concerns the use of an indazole-3-carboxamide compoundor salts or analogs thereof, in the treatment of cancer, particularlycolon, ovarian, pancreatic, breast, liver, prostate and hematologiccancers.

Description of the Related Art

Pattern formation is the activity by which embryonic cells form orderedspatial arrangements of differentiated tissues. Speculation on themechanisms underlying these patterning effects usually centers on thesecretion of a signaling molecule that elicits an appropriate responsefrom the tissues being patterned. More recent work aimed at theidentification of such signaling molecules implicates secreted proteinsencoded by individual members of a small number of gene families.

A longstanding idea in cancer biology is that cancers arise and grow dueto the formation of cancer stem cells, which may constitute only aminority of the cells within a tumor but are nevertheless critical forits propagation. Stem cells are appealing as the cell of origin forcancer because of their pre-existing capacity for self-renewal and forunlimited replication. In addition, stem cells are relatively long-livedin comparison to other cells within tissues, providing a greateropportunity to accumulate the multiple additional mutations that may berequired to increase the rate of cell proliferation and produceclinically significant cancers. Of particular recent interest in theorigin of cancer is the observation that the Wnt signaling pathway,which has been implicated in stem cell self-renewal in normal tissues,upon continuous activation has also been associated with the initiationand growth of many types of cancer. This pathway thus provides apotential link between the normal self-renewal of stem cells and theaberrantly regulated proliferation of cancer stem cells.

The Wnt growth factor family includes more than 10 genes identified inthe mouse and at least 19 genes identified in the human. Members of theWnt family of signaling molecules mediate many important short- andlong-range patterning processes during invertebrate and vertebratedevelopment. The Wnt signaling pathway is known for its important rolein the inductive interactions that regulate growth and differentiation,and plays important roles in the homeostatic maintenance ofpost-embryonic tissue integrity. Wnt stabilizes cytoplasmic β-catenin,which stimulates the expression of genes including c-myc, c jun, fra-1,and cyclin D1. In addition, misregulation of Wnt signaling can causedevelopmental defects and is implicated in the genesis of several humancancers. More recently, the Wnt pathway has been implicated in themaintenance of stem or progenitor cells in a growing list of adulttissues that now includes skin, blood, gut, prostate, muscle and thenervous system.

Pathological activation of the Wnt pathway is also believed to be theinitial event leading to colorectal cancer in over 85% of all sporadiccases in the Western world. Activation of the Wnt pathway has also beenextensively reported for hepatocellular carcinoma, breast cancer,ovarian cancer, pancreatic cancer, melanomas, mesotheliomas, lymphomasand leukemias. In addition to cancer, inhibitors of the Wnt pathway canbe used for stem cell research or for the treatment of any diseasescharacterized by aberrant Wnt activation such as diabetic retinopathy,pulmonary fibrosis, rheumatoid arthritis, scleroderma as well as mycoticand viral infections and bone and cartilage diseases. As such, it is atherapeutic target that is of great interest to the field.

In addition to cancer, there are many cases of genetic diseases due tomutations in Wnt signaling components. Examples of some of the manydiseases are Alzheimer's disease [Proc. Natl. Acad. Set. USA (2007),104(22), 9434-9], osteoarthritis, polyposis coli [Science (1991),253(5020), 665-669], bone density and vascular defects in the eye(osteoporosis-pseudoglioma syndrome, OPPG) [N. Engl. J. Med. (2002),346(20), 1513-21], familial exudative vitreoretinopathy [Hum. Mutat.(2005), 26(2), 104-12], retinal angiogenesis [Nat. Genet. (2002), 32(2),326-30], early coronary disease [Science (2007), 315(5816), 1278-82],tetra-amelia syndrome [Am. J. Hum. Genet. (2004), 74(3), 558-63],Müllerian-duct regression and virilization [Engl. J. Med. (2004),351(8), 792-8], SERKAL syndrome [Am. J. Hum. Genet. (2008), 82(1),39-47], diabetes mellitus type 2 [Am. J. Hum. Genet. (2004), 75(5),832-43; N. Engl. J. Med. (2006), 355(3), 241-50], Fuhrmann syndrome [Am.J. Hum. Genet. (2006), 79(2), 402-8], Al-Awadi/Raas-Rothschild/Schinzelphocomelia syndrome [Am. J. Hum. Genet. (2006), 79(2), 402-8],odonto-onycho-dermal dysplasia [Am. J. Hum. Genet. (2007), 81(4),821-8], obesity [Diabetologia (2006), 49(4), 678-84], split-hand/footmalformation [Hum. Mol. Genet. (2008), 17(17), 2644-53], caudalduplication syndrome [Am. J. Hum. Genet. (2006), 79(1), 155-62], toothagenesis [Am. J. Hum. Genet. (2004), 74(5), 1043-50], Wilms tumor[Science (2007), 315(5812), 642-5], skeletal dysplasia [Nat. Genet.(2009), 41(1), 95-100], focal dermal hypoplasia [Nat. Genet. (2007),39(7), 836-8], autosomal recessive anonychia [Nat. Genet. (2006),38(11), 1245-7], neural tube defects [A. Engl. J. Med. (2007), 356(14),1432-7], alpha-thalassemia (ATRX) syndrome [The Journal of Neuroscience(2008), 28(47), 12570-12580], fragile X syndrome [PLoS Genetics (2010),6(4), el000898], ICF syndrome, Angelman syndrome [Brain ResearchBulletin (2002), 57(1), 109-119], Prader-Willi syndrome [Journal ofNeuroscience (2006), 26(20), 5383-5392], Beckwith-Wiedemann Syndrome[Pediatric and Developmental Pathology (2003), 6(4), 299-306] and Rettsyndrome.

Regulation of cell signaling by the Wnt signaling pathway is criticalfor the formation of neuronal circuits. Wnt pathway modulates in neuraltissue, among other things, axon pathfinding, dendritic development, andsynaptic assembly. Through different receptors, Wnt pathway activatesand/or regulates diverse signaling pathways and other processes thatlead to local changes on the cytoskeleton or global cellular changesinvolving nuclear function. Recently, a link between neuronal activity,essential for the formation and refinement of neuronal connections, andWnt signaling has been uncovered. Indeed, neuronal activity regulatesthe release of various Wnt proteins and the localization of theirreceptors. Wnt pathway mediates synaptic structural changes induced byneuronal activity or experience. Evidence suggests that dysfunction inWnt signaling contributes to neurological disorders [Brain ResearchReviews (2000), 33(1), 1-12; Oncogene (2006) 25(57), 7545-7553;Molecular Neurodegeneration (2008), 3, 9; Neurobiology of Disease(2010), 38(2), 148-153; Journal of Neurodevelopmental Disorders (2011),3(2), 162-174 and Cold Spring Harbor Perspectives in Biology February(2012), 4(2)].

SUMMARY OF THE INVENTION

The present invention makes available methods and reagents, involvingcontacting a cell with an agent, such as an aromatic compound, in asufficient amount to antagonize Wnt activity, e.g., to reverse orcontrol an aberrant growth state or correct a genetic disorder due tomutations in Wnt signaling components.

Some embodiments disclosed herein include Wnt inhibitors containing anindazole-3-carboxamide core. Other embodiments disclosed herein includepharmaceutical compositions and methods of treatment using thesecompounds.

One embodiment disclosed herein includes a compound having the structureof formula I:

In some embodiments of formula (I):

R¹, R² and R⁴ are independently selected from the group consisting of H,C₁₋₉ alkyl, halide, —N(R¹⁰)₂, —XR¹⁰, CN, —OCF₃ and —CF₃;

R³ is selected from the group consisting of carbocyclylR⁶,heterocyclylR⁶, arylR⁶ and heteroarylR⁶;

with the proviso that when R³ is heteroaryl, the heteroaryl is notselected from the group consisting of isoquinoline,1H-pyrrolo[2,3-c]pyridine and tetrazole;

R⁵ is selected from the group consisting of —(C₁₋₉alkyl)_(n)carbocyclylR⁷, —(C₁₋₉ alkyl)_(n)heterocyclylR⁷, —(C₁₋₉alkyl)_(n)arylR⁷ and —(C₁₋₉ alkyl)_(n)heteroarylR⁷;

with the proviso that R⁵ is not 4-pyridylR⁷ when R¹, R² and R⁴ are H, R³is selected from the group consisting of 3-pyridylR⁶, 4-pyridylR⁶,2-pyridylR⁶, phenylR⁶, thiazoleR⁶, imidazoleR⁶, pyrimidineR⁶, oxazoleR⁶,

and, and R⁶ and R⁷ are both H.

with the proviso that R⁵ is not —(CH₂)(3-pyridyl)R⁷ when R¹, R² and R⁴are H, R³ is selected from the group consisting of 3-pyridylR⁶,4-pyridylR⁶ and thiazoleR⁶, and R⁶ and R⁷ are both H;

with the proviso that R⁵ is not phenylR⁷ when R¹, R² and R⁴ are H, R³ is4-pyridylR⁶ and R⁶ and R⁷ are both H;

with the proviso that R³ is not 3-pyridylR⁶ when R¹, R² and R⁴ are H, R⁵is selected from the group consisting of phenylR⁷,

and R⁶ and R⁷ are both H;

with the proviso that R³ is not oxazoleR⁶ when R¹, R² and R⁴ are H, R⁵is selected from the group consisting of

and R⁶ is H;

with the proviso that R³ is not thiazoleR⁶ when R¹, R² and R⁴ are H, R⁵is selected from the group consisting of

and R⁶ is H;

each R⁶ is 1-5 substituents each selected from the group consisting ofH, C₁₋₉ alkyl, halide, amino, —OCF₃, —CF₃, —CN, —XR¹⁰, —(C₁₋₉alkyl)_(n)carbocyclylR⁸, —(C₁₋₉ alkyl)_(n)heterocyclylR⁸, —(C₁₋₉alkyl)_(n)arylR⁸, —(C₁₋₉ alkyl)_(n)heteroarylR⁸, —C(═O)R¹¹,—N(R¹⁰)C(═O)R¹¹, —(C₁₋₉ alkyl)_(n)N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)N(R¹⁰)SO₂R¹¹and —SO₂R¹¹;

each R⁷ is 1-5 substituents each selected from the group consisting ofH, C₁₋₉ alkyl, halide, amino, —OCF₃, —CF₃, —CN, —XR¹⁰, —(C₁₋₉alkyl)_(n)carbocyclylR⁹, —(C₁₋₉ alkyl)_(n)heterocyclylR⁹, —(C₁₋₉alkyl)_(n)arylR⁹, —(C₁₋₉ alkyl)_(n)heteroarylR⁹, —C(═O)R¹¹,—N(R¹⁰)C(═O)R¹¹, —(C₁₋₉ alkyl)_(n)N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)N(R¹⁰)SO₂R¹¹and —SO₂R¹¹;

each R⁸ is 1-5 substituents each selected from the group consisting ofH, C₁₋₃ alkyl, halide, amino, OCF₃, —CF₃—CN, —XR¹², —C(═O)R¹³,—N(R¹²)C(═O)R¹³, —(C₁₋₉ alkyl)_(n)N(R¹²)₂, —(C₁₋₉ alkyl)_(n)N(R¹²)SO₂R¹³and —SO₂R¹³;

each R⁹ is 1-5 substituents each selected from the group consisting ofH, C₁₋₃ alkyl, halide, amino, —OCF₃, —CF₃—CN, —XR¹², —C(═O)R¹³,—N(R¹²)C(═O)R¹³, —(C₁₋₉ alkyl)_(n)N(R¹²)₂, —(C₁₋₉ alkyl)_(n)N(R¹²)SO₂R¹³and —SO₂R¹³;

each R¹⁰ is independently selected from the group consisting of H, C₁₋₉alkyl, —(C₁₋₉ alkyl)_(n)N(R¹⁴)₂, —(C₁₋₉ alkyl)_(n)carbocyclylR⁸, —(C₁₋₉alkyl)_(n)heterocyclylR⁸, —(C₁₋₉ alkyl)_(n)arylR⁸ and —(C₁₋₉alkyl)_(n)heteroarylR⁸;

each R¹¹ is independently selected from the group consisting of C₁₋₉alkyl, —N(R¹⁴)₂, —(C₁₋₉ alkyl)_(n)carbocyclylR⁸, —(C₁₋₉alkyl)_(n)heterocyclylR⁸, —(C₁₋₉ alkyl)_(n)arylR⁸ and —(C₁₋₉alkyl)_(n)heteroarylR⁸;

each R¹² is independently selected from the group consisting of H, C₁₋₉alkyl, —(C₁₋₉ alkyl)_(n)N(R¹⁴)₂, —(C₁₋₉ alkyl)_(n)carbocyclyl, —(C₁₋₉alkyl)_(n)heterocyclyl, —(C₁₋₉ alkyl)_(n)aryl and —(C₁₋₉alkyl)_(n)heteroaryl;

each R¹³ is independently selected from the group consisting of C₁₋₉alkyl, —N(R¹⁴)₂, —(C₁₋₉ alkyl)_(n)carbocyclyl, —(C₁₋₉alkyl)_(n)heterocyclyl, —(C₁₋₉ alkyl)_(n)aryl and —(C₁₋₉alkyl)_(n)heteroaryl;

each R¹⁴ is independently selected from the group consisting of H, C₁₋₃alkyl, carbocyclyl and aryl;

each X is selected from the group consisting of a bond, —O— and —S—; andeach n is 0 or 1.

Some embodiments include stereoisomers and pharmaceutically acceptablesalts of a compound of general formula (I).

Some embodiments include pro-drugs of a compound of general formula (I).

Some embodiments of the present invention include pharmaceuticalcompositions comprising a compound of general formula (I) or in apharmaceutically acceptable carrier, diluent, or excipient.

Other embodiments disclosed herein include methods of inhibiting one ormore members of the Wnt pathway, including one or more Wnt proteins byadministering to a subject affected by a disorder or disease in whichaberrant Wnt signaling is implicated, such as cancer and other diseasesassociated with abnormal angiogenesis, cellular proliferation, cellcycling and mutations in Wnt signaling components, a compound accordingto formula (I). Accordingly, the compounds and compositions providedherein can be used to treat cancer, to reduce or inhibit angiogenesis,to reduce or inhibit cellular proliferation and correct a geneticdisorder due to mutations in Wnt signaling components. Non-limitingexamples of diseases which can be treated with the compounds andcompositions provided herein include a variety of cancers, diabeticretinopathy, pulmonary fibrosis, rheumatoid arthritis, scleroderma,mycotic and viral infections, osteochondrodysplasia, Alzheimer'sdisease, lung disease, osteoarthritis, polyposis coli,osteoporosis-pseudoglioma syndrome, familial exudativevitreoretinopathy, retinal angiogenesis, early coronary disease,tetra-ameliasyndrome, Müllerian-duct regression and virilization, SERKALsyndrome, diabetes mellitus type 2, Fuhrmann syndrome,Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletaldysplasia, focal dermal hypoplasia, autosomal recessive anonychia,neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile Xsyndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome,Beckwith-Wiedemann Syndrome, Norrie disease and Rett syndrome.

Some embodiments of the present invention include methods to prepare acompound of general formula (I).

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention, as claimed.

DETAILED DESCRIPTION OF THE INVENTION

Compositions and methods for inhibiting one or more members of the Wntpathway, including one or more Wnt proteins would be of tremendousbenefit. Certain embodiments provide such compositions and methods.

Some embodiments relate to a method for treating a disease including,but not limited to, cancers, diabetic retinopathy, pulmonary fibrosis,rheumatoid arthritis, scleroderma, mycotic and viral infections, boneand cartilage diseases, Alzheimer's disease, lung disease,osteoarthritis, polyposis coli, bone density and vascular defects in theeye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudativevitreoretinopathy, retinal angiogenesis, early coronary disease,tetra-amelia, Müllerian-duct regression and virilization, SERKALsyndrome, type II diabetes, Fuhrmann syndrome,Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia,focal dermal hypoplasia, autosomal recessive anonychia, neural tubedefects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICFsyndrome, Angelman's syndrome, Prader-Willi syndrome, Beckwith-WiedemannSyndrome, Norrie disease and Rett syndrome.

In some embodiments, pharmaceutical compositions are provided that areeffective for treatment of a disease of an animal, e.g., a mammal,caused by the pathological activation or mutations of the Wnt pathway.The composition includes a pharmaceutically acceptable carrier and a Wntpathway inhibitor as described herein.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art to which this disclosure belongs. All patents, applications,published applications, and other publications are incorporated byreference in their entirety. In the event that there is a plurality ofdefinitions for a term herein, those in this section prevail unlessstated otherwise.

In this specification and in the claims, the following terms have themeanings as defined. As used herein, “alkyl” means a branched, orstraight chain chemical group containing only carbon and hydrogen, suchas methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl andpentyl. Alkyl groups can either be unsubstituted or substituted with oneor more substituents, e.g., halide, alkoxy, acyloxy, amino, amido,cyano, nitro, hydroxyl, mercapto, carboxy, carbonyl, benzyloxy, aryl,heteroaryl, or other functionality that may be suitably blocked, ifnecessary for purposes of the invention, with a protecting group. Alkylgroups can be saturated or unsaturated (e.g., containing —C═C— or —C≡C—subunits), at one or several positions. Typically, alkyl groups willcomprise 1 to 9 carbon atoms, preferably 1 to 6, more preferably 1 to 4,and most preferably 1 to 2 carbon atoms.

As used herein, “carbocyclyl” means a cyclic ring system containing onlycarbon atoms in the ring system backbone, such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. Carbocyclyls mayinclude multiple fused rings. Carbocyclyls may have any degree ofsaturation provided that at least one ring in the ring system is notaromatic. Carbocyclyl groups can either be unsubstituted or substitutedwith one or more substituents, e.g., alkyl, halide, alkoxy, acyloxy,amino, amido, cyano, nitro, hydroxyl, mercapto, carboxy, carbonyl,benzyloxy, aryl, heteroaryl, or other functionality that may be suitablyblocked, if necessary for purposes of the invention, with a protectinggroup. Typically, carbocyclyl groups will comprise 3 to 10 carbon atoms,preferably 3 to 6.

As used herein, “lower alkyl” means a subset of alkyl having 1 to 3carbon atoms, and thus is a hydrocarbon substituent, which is linear, orbranched. Examples of lower alkyl include methyl, ethyl, n-propyl andisopropyl. Likewise, radicals using the terminology “lower” refer toradicals preferably with 1 to about 3 carbons in the alkyl portion ofthe radical.

As used herein, “amido” means a H—CON— or alkyl-CON—, carbocyclyl-CON—,aryl-CON—, heteroaryl-CON— or heterocyclyl-CON group wherein the alkyl,carbocyclyl, aryl or heterocyclyl group is as herein described.

As used herein, “aryl” means an aromatic radical having a single-ring(e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl)with only carbon atoms present in the ring backbone. Aryl groups caneither be unsubstituted or substituted with one or more substituents,e.g., alkyl, amino, cyano, hydroxyl, lower alkyl, haloalkyl, alkoxy,nitro, halo, mercapto, and other substituents. A preferred carbocyclicaryl is phenyl.

As used herein, the term “heteroaryl” means an aromatic radical havingone or more heteroatom(s) (e.g., N, O, or S) in the ring backbone andmay include a single ring (e.g., pyridine) or multiple condensed rings(e.g., quinoline). Heteroaryl groups can either be unsubstituted orsubstituted with one or more substituents, e.g., amino, cyano, hydroxyl,lower alkyl, haloalkyl, alkoxy, nitro, halo, mercapto, and othersubstituents. Examples of heteroaryl include thienyl, pyridinyl, furyl,oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl,pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl,pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl,benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl,indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl,thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl,quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl,pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl,pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridinyl, tetrazolyl, andothers.

In these definitions it is clearly contemplated that substitution on thearyl and heteroaryl rings is within the scope of certain embodiments.Where substitution occurs, the radical is called substituted aryl orsubstituted heteroaryl. Preferably one to three and more preferably oneor two substituents occur on the aryl ring. Though many substituentswill be useful, preferred substituents include those commonly found inaryl compounds, such as alkyl, cycloalkyl, hydroxy, alkoxy, cyano, halo,haloalkyl, mercapto and the like.

As used herein, “amide” includes both RNR′CO— (in the case of R=alkyl,alkaminocarbonyl-) and RCONR′— (in the case of R=alkyl, alkylcarbonylamino-).

As used herein, the term “ester” includes both ROCO— (in the case ofR=alkyl, alkoxy carbonyl-) and RCOO— (in the case of R=alkyl,alkylcarbonyloxy-).

As used herein, “acyl” means an H—CO— or alkyl-CO—, carbocyclyl-CO—,aryl-CO—, heteroaryl-CO— or heterocyclyl-CO— group wherein the alkyl,carbocyclyl, aryl or heterocyclyl group is as herein described.Preferred acyls contain a lower alkyl. Exemplary alkyl acyl groupsinclude formyl, acetyl, propanoyl, 2-methylpropanoyl, t-butylacetyl,butanoyl and palmitoyl.

As used herein, “halo”, “halide” or “halogen” is a chloro, bromo, fluoroor iodo atom radical. Chloro, bromo and fluoro are preferred halides.Most preferred halide is fluorine.

As used herein, “haloalkyl” means a hydrocarbon substituent, which islinear or branched or cyclic alkyl, alkenyl or alkynyl substituted withchloro, bromo, fluoro or iodo atom(s). Most preferred of these arefluoroalkyls, wherein one or more of the hydrogen atoms have beensubstituted by fluoro. Preferred haloalkyls are of 1 to about 3 carbonsin length, more preferred haloalkyls are 1 to about 2 carbons, and mostpreferred are 1 carbon in length. The skilled artisan will recognizethen that as used herein, “haloalkylene” means a diradical variant ofhaloalkyl, such diradicals may act as spacers between radicals, otheratoms, or between the parent ring and another functional group.

As used herein, “heterocyclyl” means a cyclic ring system comprising atleast one heteroatom in the ring system backbone. Heterocyclyls mayinclude multiple fused rings. Heterocyclyls may have any degree ofsaturation provided that at least one ring in the ring system is notaromatic. Heterocyclyls may be substituted or unsubstituted with one ormore substituents, e.g., alkyl, halide, alkoxy, acyloxy, amino, amido,cyano, nitro, hydroxyl, mercapto, carboxy, carbonyl, benzyloxy, aryl,heteroaryl, and other substituents, and are attached to other groups viaany available valence, preferably any available carbon or nitrogen. Morepreferred heterocycles are of 5-7 members. In six membered monocyclicheterocycles, the heteroatom(s) are selected from one up to three of O,N or S, and wherein when the heterocycle is five membered, preferably ithas one or two heteroatoms selected from O, N, or S. Examples ofheterocyclyl include azirinyl, aziridinyl, azetidinyl, oxetanyl,thietanyl, 1,4,2-dithiazolyl, 1,3-benzodioxolyl, dihydroisoindolyl,dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl,dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl,dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl,isoindolinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl,pyrrolidinyl, tetrahydrofuryl, tetrahydropyridinyl, oxazinyl, thiazinyl,thiinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl,piperidinyl, pyrazolidinyl imidazolidinyl, thiomorpholinyl, and others.

As used herein, “substituted amino” means an amino radical which issubstituted by one or two alkyl, cycloalkyl, aryl, heteroaryl orheterocyclyl groups, wherein the alkyl, aryl, heteroaryl or heterocyclylare defined as above.

As used herein, “substituted thiol” means RS— group wherein R is analkyl, an aryl, heteroaryl or a heterocyclyl group, wherein the alkyl,cycloalkyl, aryl, heteroaryl or heterocyclyl are defined as above.

As used herein, “sulfonyl” means an alkylSO₂, arylSO₂, heteroarylSO₂,carbocyclyl SO₂, or heterocyclyl-SO₂ group wherein the alkyl,carbocyclyl, aryl, heteroaryl or heterocyclyl are defined as above.

As used herein, “sulfamido” means an alkyl-N—S(O)₂N—, aryl-NS(O)₂N—,heteroaryl-NS(O)₂N—, carbocyclyl-NS(O)₂N or heterocyclyl-NS(O)₂N— groupwherein the alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl groupis as herein described.

As used herein, “sulfonamido” means an alkyl-S(O)₂N—, aryl-S(O)₂N—,heteroaryl-S(O)₂N—, carbocyclyl-S(O)₂N— or heterocyclyl-S(O)₂N— groupwherein the alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl groupis as herein described.

As used herein, “ureido” means an alkyl-NCON—, aryl-NCON—,heteroaryl-NCON—, carbocyclyl-NCON— or heterocyclyl-NCON— group whereinthe alkyl, carbocyclyl, aryl, heteroaryl or heterocyclyl group is asherein described.

As used herein, when two groups are indicated to be “linked” or “bonded”to form a “ring,” it is to be understood that a bond is formed betweenthe two groups and may involve replacement of a hydrogen atom on one orboth groups with the bond, thereby forming a carbocyclyl, heterocyclyl,aryl, or heteroaryl ring. The skilled artisan will recognize that suchrings can and are readily formed by routine chemical reactions, and itis within the purview of the skilled artisan to both envision such ringsand the methods of their formations. Preferred are rings having from 3-7members, more preferably 5 or 6 members. As used herein the term “ring”or “rings” when formed by the combination of two radicals refers toheterocyclic, carbocyclic, aryl, or heteroaryl rings.

The skilled artisan will recognize that some structures described hereinmay be resonance forms or tautomers of compounds that may be fairlyrepresented by other chemical structures, even when kinetically; theartisan recognizes that such structures are only a very small portion ofa sample of such compound(s). Such compounds are clearly contemplatedwithin the scope of this invention, though such resonance forms ortautomers may not be explicitly represented herein.

The compounds provided herein may encompass various stereochemicalforms. The compounds also encompasses diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds. Separation ofthe individual isomers or selective synthesis of the individual isomersis accomplished by application of various methods which are well knownto practitioners in the art. Unless otherwise indicated, when adisclosed compound is named or depicted by a structure withoutspecifying the stereochemistry and has one or more chiral centers, it isunderstood to represent all possible stereoisomers of the compound.

The term “administration” or “administering” refers to a method ofgiving a dosage of a compound or pharmaceutical composition to avertebrate or invertebrate, including a mammal, a bird, a fish, or anamphibian, where the method is, e.g., orally, subcutaneously,intravenously, intranasally, topically, transdermally,intraperitoneally, intramuscularly, intrapulmonarilly, vaginally,rectally, ontologically, neuro-otologically, intraocularly,subconjuctivally, via anterior eye chamber injection, intravitreally,intraperitoneally, intrathecally, intracystically, intrapleurally, viawound irrigation, intrabuccally, intra-abdominally, intra-articularly,intra-aurally, intrabronchially, intracapsularly, intrameningeally, viainhalation, via endotracheal or endobronchial instillation, via directinstillation into pulmonary cavities, intraspinally, intrasynovially,intrathoracically, via thoracostomy irrigation, epidurally,intratympanically, intracisternally, intravascularly,intraventricularly, intraosseously, via irrigation of infected bone, orvia application as part of any admixture with a prosthetic devices. Thepreferred method of administration can vary depending on variousfactors, e.g., the components of the pharmaceutical composition, thesite of the disease, the disease involved, and the severity of thedisease.

A “diagnostic” as used herein is a compound, method, system, or devicethat assists in the identification and characterization of a health ordisease state. The diagnostic can be used in standard assays as is knownin the art.

The term “mammal” is used in its usual biological sense. Thus, itspecifically includes humans, cattle, horses, dogs, and cats, but alsoincludes many other species.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” includes any and all solvents, co-solvents,complexing agents, dispersion media, coatings, antibacterial andantifungal agents, isotonic and absorption delaying agents and the likewhich are not biologically or otherwise undesirable. The use of suchmedia and agents for pharmaceutically active substances is well known inthe art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions. In addition, various adjuvantssuch as are commonly used in the art may be included. These and othersuch compounds are described in the literature, e.g., in the MerckIndex, Merck & Company, Rahway, N.J. Considerations for the inclusion ofvarious components in pharmaceutical compositions are described, e.g.,in Gilman et al. (Eds.) (2010); Goodman and Gilman's: ThePharmacological Basis of Therapeutics. 12th Ed. The McGraw-HillCompanies.

The term “pharmaceutically acceptable salt” refers to salts that retainthe biological effectiveness and properties of the compounds of thepreferred embodiments and, which are not biologically or otherwiseundesirable. In many cases, the compounds of the preferred embodimentsare capable of forming acid and/or base salts by virtue of the presenceof amino and/or carboxyl groups or groups similar thereto.Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids. Inorganic acids from which salts canbe derived include, for example, hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acidsfrom which salts can be derived include, for example, acetic acid,propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and thelike. Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases. Inorganic bases from which salts can bederived include, for example, sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum, and thelike; particularly preferred are the ammonium, potassium, sodium,calcium and magnesium salts. Organic bases from which salts can bederived include, for example, primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines, basic ion exchange resins, and the like, specificallysuch as isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, and ethanolamine. Many such salts are known in the art,as described in World Patent Publication 87/05297, Johnston et al.,published Sep. 11, 1987 (incorporated by reference herein).

“Solvate” refers to the compound formed by the interaction of a solventand a Wnt pathway inhibitor, a metabolite, or salt thereof. Suitablesolvates are pharmaceutically acceptable solvates including hydrates.

“Subject” as used herein, means a human or a non-human mammal, e.g., adog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-humanprimate or a bird, e.g., a chicken, as well as any other vertebrate orinvertebrate.

By “therapeutically effective amount” or “pharmaceutically effectiveamount” is one which is sufficient to achieve the desired effect and mayvary according to the nature and severity of the disease condition, andthe potency of the compound. “Therapeutically effective amount” is alsointended to include one or more of the compounds of formula (I) incombination with one or more other agents that are effective to inhibitWnt related diseases and/or conditions. The combination of compounds ispreferably a synergistic combination. Synergy, as described, forexample, by Chou and Talalay, Advances in Enzyme Regulation (1984), 22,27-55, occurs when the effect of the compounds when administered incombination is greater than the additive effect of the compounds whenadministered alone as a single agent. In general, a synergistic effectis most clearly demonstrated at sub-optimal concentrations of thecompounds. It will be appreciated that different concentrations may beemployed for prophylaxis than for treatment of an active disease. Thisamount can further depend upon the patient's height, weight, sex, ageand medical history.

A therapeutic effect relieves, to some extent, one or more of thesymptoms of the disease, and includes curing a disease. “Curing” meansthat the symptoms of active disease are eliminated. However, certainlong-term or permanent effects of the disease may exist even after acure is obtained (such as extensive tissue damage).

“Treat,” “treatment,” or “treating,” as used herein refers toadministering a pharmaceutical composition for therapeutic purposes. Theterm “therapeutic treatment” refers to administering treatment to apatient already suffering from a disease thus causing a therapeuticallybeneficial effect, such as ameliorating existing symptoms, preventingadditional symptoms, ameliorating or preventing the underlying metaboliccauses of symptoms, postponing or preventing the further development ofa disorder and/or reducing the severity of symptoms that will or areexpected to develop.

Compounds

The compounds and compositions described herein can be used asanti-proliferative agents, e.g., anti-cancer and anti-angiogenesisagents, and as inhibitors of the Wnt signaling pathway, e.g., fortreating diseases or disorders associated with aberrant Wnt signaling.In addition, the compounds can be used as inhibitors of one or morekinases, kinase receptors, or kinase complexes. Such compounds andcompositions are also useful for controlling cellular proliferation,differentiation, and/or apoptosis.

Some embodiments of the present invention include compounds, salts,pharmaceutically acceptable salts or pro-drug thereof of formula (I):

In some embodiments of formula I, R¹, R² and R⁴ are independentlyselected from the group consisting of H, C₁₋₉ alkyl, halide, —N(R¹⁰)₂,—XR¹⁰, CN, —OCF₃ and —CF₃.

In some embodiments of formula I, R³ is selected from the groupconsisting of carbocyclylR⁶, heterocyclylR⁶, arylR⁶ and heteroarylR⁶.

In some embodiments of formula I, when R³ is heteroaryl, the heteroarylis not selected from the group consisting of isoquinoline,1H-pyrrolo[2,3-c]pyridine and tetrazole.

In some embodiments of formula I, R⁵ is selected from the groupconsisting of —(C₁₋₉ alkyl)_(n)carbocyclylR⁷, —(C₁₋₉alkyl)_(n)heterocyclylR⁷, —(C₁₋₉ alkyl)_(n)arylR⁷ and —(C₁₋₉alkyl)_(n)heteroarylR⁷.

In some embodiments of formula I, R⁵ is not 4-pyridylR⁷ when R¹, R² andR⁴ are H, R³ is selected from the group consisting of 3-pyridylR⁶,4-pyridylR⁶, 2-pyridylR⁶, phenylR⁶, thiazoleR⁶, imidazoleR⁶,pyrimidineR⁶, oxazoleR⁶,

and R⁶ and R⁷ are both H.

In some embodiments of formula I, R⁵ is not —(CH₂)(3-pyridyl)R⁷ when R¹,R² and R⁴ are H, R³ is selected from the group consisting of3-pyridylR⁶, 4-pyridylR⁶ and thiazoleR⁶, and R⁶ and R⁷ are both H.

In some embodiments of formula I, R⁵ is not phenylR⁷ when R¹, R² and R⁴are H, R³ is 4-pyridylR⁶ and R⁶ and R⁷ are both H.

In some embodiments of formula I, R³ is not 3-pyridylR⁶ when R¹, R² andR⁴ are H, R⁵ is selected from the group consisting of phenylR⁷,

and R⁶ and R⁷ are both H.

In some embodiments of formula I, R³ is not oxazoleR⁶ when R¹, R² and R⁴are H, R⁵ is selected from the group consisting of

and R⁶ is H.

In some embodiments of formula I, R³ is not thiazoleR⁶ when R¹, R² andR⁴ are H, R⁵ is selected from the group consisting of

and R is H.

In some embodiments of formula I, each R⁶ is 1-5 substituents eachselected from the group consisting of H, C₁₋₉ alkyl, halide, amino,—OCF₃, —CF₃, —CN, —XR¹⁰, —(C₁₋₉ alkyl)_(n)carbocyclylR⁸, —(C₁₋₉alkyl)_(n)heterocyclylR⁸, —(C₁₋₉ alkyl)_(n)arylR⁸, —(C₁₋₉alkyl)_(n)heteroarylR⁸, —C(═O)R¹¹, —N(R¹⁰)C(═O)R¹¹, —(C₁₋₉alkyl)_(n)N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)N(R¹⁰)SO₂R¹¹ and —SO₂R¹¹.

In some embodiments of formula I, each R⁷ is 1-5 substituents eachselected from the group consisting of H, C₁₋₉ alkyl, halide, amino,—OCF₃, —CF₃, —CN, —XR¹⁰, —(C₁₋₉ alkyl)_(n)carbocyclylR⁹, —(C₁₋₉alkyl)_(n)heterocyclylR⁹, —(C₁₋₉ alkyl)_(n)arylR⁹, —(C₁₋₉alkyl)_(n)heteroarylR⁹, —C(═O)R¹¹, —N(R¹⁰)C(═O)R¹¹, —(C₁₋₉alkyl)_(n)N(R¹⁰)₂, —(C₁₋₉ alkyl)_(n)N(R¹⁰)SO₂R¹¹ and —SO₂R¹¹.

In some embodiments of formula I, each R⁸ is 1-5 substituents eachselected from the group consisting of H, C₁₋₃ alkyl, halide, amino,OCF₃, —CF₃—CN, —XR¹², —C(═O)R¹³, —N(R¹²)C(═O)R¹³, —(C₁₋₉alkyl)_(n)N(R¹²)₂, —(C₁₋₉ alkyl)_(n)N(R¹²)SO₂R¹³ and —SO₂R¹³.

In some embodiments of formula I, each R⁹ is 1-5 substituents eachselected from the group consisting of H, C₁₋₃ alkyl, halide, amino,—OCF₃, —CF₃—CN, —XR¹², —C(═O)R¹³, —N(R¹²)C(═O)R¹³, —(C₁₋₉alkyl)_(n)N(R¹²)₂, —(C₁₋₉ alkyl)_(n)N(R¹²)SO₂R¹³ and —SO₂R¹³.

In some embodiments of formula I, each R¹⁰ is independently selectedfrom the group consisting of H, C₁₋₉ alkyl, —(C₁₋₉ alkyl)_(n)N(R¹⁴)₂,—(C₁₋₉ alkyl)_(n)carbocyclylR⁸, —(C₁₋₉ alkyl)_(n)heterocyclylR⁸, —(C₁₋₉alkyl)_(n)arylR⁸ and —(C₁₋₉ alkyl)_(n)heteroarylR⁸.

In some embodiments of formula I, each R¹¹ is independently selectedfrom the group consisting of C₁₋₉ alkyl, —N(R¹⁴)₂, —(C₁₋₉alkyl)_(n)carbocyclylR⁸, —(C₁₋₉ alkyl)_(n)heterocyclylR⁸, —(C₁₋₉alkyl)_(n)arylR⁸ and —(C₁₋₉ alkyl)_(n)heteroarylR⁸.

In some embodiments of formula I, each R¹² is independently selectedfrom the group consisting of H, C₁₋₉ alkyl, —(C₁₋₉ alkyl)_(n)N(R¹⁴)₂,—(C₁₋₉ alkyl)_(n)carbocyclyl, —(C₁₋₉ alkyl)_(n)heterocyclyl, —(C₁₋₉alkyl)_(n)aryl and —(C₁₋₉ alkyl)_(n)heteroaryl.

In some embodiments of formula I, each R¹³ is independently selectedfrom the group consisting of C₁₋₉ alkyl, —N(R¹⁴)₂, —(C₁₋₉alkyl)_(n)carbocyclyl, —(C₁₋₉ alkyl)_(n)heterocyclyl, —(C₁₋₉alkyl)_(n)aryl and —(C₁₋₉ alkyl)_(n)heteroaryl.

In some embodiments of formula I, each R¹⁴ is independently selectedfrom the group consisting of H, C₁₋₃ alkyl, carbocyclyl and aryl.

In some embodiments of formula I, each X is selected from the groupconsisting of a bond, —O— and —S—.

In some embodiments of formula I, each n is 0 or 1.

In some embodiments of formula I, X is O.

In some embodiments of formula I, R¹, R² and R⁴ are H.

Some embodiments of the present invention include compounds, salts,pharmaceutically acceptable salts or pro-drug thereof of formula (Ia):

In some embodiments of formula Ia, R³ is selected from the groupconsisting of arylR⁶ and heteroarylR⁶.

In some embodiments of formula Ia, when R³ is heteroaryl, the heteroarylis not selected from the group consisting of isoquinoline,1H-pyrrolo[2,3-c]pyridine and tetrazole.

In some embodiments of formula Ia, R⁵ is selected from the groupconsisting of -carbocyclylR⁷, -heterocyclylR⁷, -arylR⁷, -heteroarylR⁷,and —(C₁₋₂ alkyl)heteroarylR⁷.

In some embodiments of formula Ia, R⁵ is not 4-pyridylR⁷ when R³ isselected from the group consisting of 3-pyridylR⁶, 4-pyridylR⁶,2-pyridylR⁶, phenylR⁶, thiazoleR⁶, imidazoleR⁶, pyrimidineR⁶, oxazoleR⁶,

and R⁶ and R⁷ are both H.

In some embodiments of formula Ia, R⁵ is not —(CH₂)(3-pyridyl)R⁷ when R³is selected from the group consisting of 3-pyridylR⁶, 4-pyridylR⁶ andthiazoleR⁶, and R⁶ and R⁷ are both H.

In some embodiments of formula Ia, R⁵ is not phenylR⁷ when R³ is4-pyridylR⁶ and R⁶ and R⁷ are both H.

In some embodiments of formula Ia, R³ is not 3-pyridylR⁶ when R⁵ isselected from the group consisting of phenylR⁷,

and R⁶ and R⁷ are both H.

In some embodiments of formula Ia, R³ is not oxazoleR⁶ when R⁵ isselected from the group consisting of

and R⁶ is H.

In some embodiments of formula Ia, R³ is not thiazoleR⁶ when R⁵ isselected from the group consisting of

and R⁶ is H.

In some embodiments of formula Ia, each R⁶ is 1-2 substituents eachselected from the group consisting of H, C₁₋₃ alkyl, halide, amino,—OCF₃, —CF₃, —CN, —OR¹⁰, —(C₁₋₂ alkyl)heterocyclylR⁸, -heterocyclylR⁸,—(C₁₋₂ alkyl)arylR⁸, —C(═O)R¹¹, —N(R¹⁰)C(═O)R¹¹ and —(C₁₋₂alkyl)N(R¹⁰)₂.

In some embodiments of formula Ia, each R⁷ is 1-2 substituents eachselected from the group consisting of H, C₁₋₃ alkyl, halide, amino,—OCF₃, —CF₃, —CN, —OR¹⁰, —(C₁₋₂ alkyl)heterocyclylR⁹, -heterocyclylR⁹,-arylR⁹, —(C₁₋₂ alkyl)arylR⁹, —C(═O)R¹¹, —N(R¹⁰)C(═O)R¹¹, —N(R¹⁰)₂,—(C₁₋₂ alkyl)N(R¹⁰)₂, —N(R¹⁰)SO₂R¹¹ and —SO₂R¹¹.

In some embodiments of formula Ia, each R⁸ is 1-2 substituents eachselected from the group consisting of H, C₁₋₃ alkyl, halide, amino,OCF₃, —CF₃—CN and —OR¹².

In some embodiments of formula Ia, each R⁹ is 1-2 substituents eachselected from the group consisting of H, C₁₋₃ alkyl, halide, amino,—OCF₃, —CF₃—CN and —OR¹².

In some embodiments of formula Ia, each R¹⁰ is independently selectedfrom the group consisting of H, C₁₋₃ alkyl, —(C₁₋₃ alkyl)N(R¹⁴)₂ and-arylR⁸.

In some embodiments of formula Ia, each R¹¹ is independently selectedfrom the group consisting of C₁₋₃ alkyl, —N(R¹⁴)₂, -carbocyclylR⁸ and-heterocyclylR⁸.

In some embodiments of formula Ia, each R¹² is independently selectedfrom the group consisting of H and C₁₋₃ alkyl.

In some embodiments of formula Ia, each R¹⁴ is independently selectedfrom the group consisting of H, C₁₋₃ alkyl and carbocyclyl.

In some embodiments of formula I or formula Ia, halide is fluorine.

In some embodiments of formula I or formula Ia, R³ is -arylR⁶.

In some embodiments of formula I or formula Ia, R³ is -heteroarylR⁶.

In some embodiments of formula I or formula Ia, R⁵ is -arylR⁷.

In some embodiments of formula I or formula Ia, R⁵ is -heteroarylR⁷.

In some embodiments of formula I or formula Ia, R⁵ is -heterocyclylR⁷.

In some embodiments of formula I or formula Ia, R³ is -heteroarylR⁶ andR⁵ is -heteroarylR⁷.

In some embodiments of formula I or formula Ia, R³ is -phenylR⁶ and R⁵is -heteroarylR⁷.

In some embodiments of formula I or formula Ia, R³ is -heteroarylR⁶ andR⁵ is -phenylR⁷.

In some embodiments of formula I or formula Ia, R³ is -3-pyridylR⁶ andR⁵ is -3-pyridylR⁷.

In some embodiments of formula I or formula Ia, R³ is -3-pyridylR⁶ andR⁵ is —CH₂-3-pyridylR⁷.

In some embodiments of formula I or formula Ia, R³ is -3-pyridylR⁶ andR⁵ is -pyridazinylR⁷.

In some embodiments of formula I or formula Ia, R³ is -3-pyridylR⁶ andR⁵ is -pyrazinylR⁷.

In some embodiments of formula I or formula Ia, R³ is -3-pyridylR⁶ andR⁵ is -pyrimidinylR⁷.

In some embodiments of formula I or formula Ia, R³ is -3-pyridylR⁶ andR⁵ is benzo[d][1,3]dioxolyl.

In some embodiments of formula I or formula Ia, R³ is -3-pyridylR⁶ andR⁵ is 2,3-dihydrobenzo[6][1,4]dioxinyl.

In some embodiments of formula I or formula Ia, the aryl is phenyl.

In some embodiments of formula I or formula Ia, when R³ is heteroaryl,the heteroaryl is 3-pyridyl.

In some embodiments of formula I or formula Ia, when R⁵ is heteroaryl,the heteroaryl is 3-pyridyl.

In some embodiments of formula I or formula Ia, when R⁵ is heteroaryl,the heteroaryl is 5-pyrimidinyl.

In some embodiments of formula I or formula Ia, when R⁵ is heteroaryl,the heteroaryl is 4-pyridazinyl.

In some embodiments of formula I or formula Ia, when R⁵ is heteroaryl,the heteroaryl is pyrazolyl.

In some embodiments of formula I or formula Ia, when R⁵ is heteroaryl,the heteroaryl is benzo[d][1,3]dioxolyl.

In some embodiments of formula I or formula Ia, when R⁵ is heteroaryl,the heteroaryl is 2,3-dihydrobenzo[6][1,4]dioxinyl.

In some embodiments of formula I or formula Ia, R⁶ is a heterocyclyl.For example, the heterocyclyl can be selected from the group consistingof morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, azetidinyland pyrrolidinyl. In certain embodiments, R⁶ is morpholinyl. In anotherembodiment, R⁶ is piperazinyl. In another embodiment, R⁶ is piperidinyl.In another embodiment, R⁶ is pyrrolidinyl.

In some embodiments of formula I or formula Ia, R⁷ is a heterocyclyl.For example, the heterocyclyl can be selected from the group consistingof morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, azetidinyland pyrrolidinyl. In certain embodiments, R⁷ is morpholinyl. In anotherembodiment, R⁷ is piperazinyl. In another embodiment, R⁷ is piperidinyl.In another embodiment, R⁷ is pyrrolidinyl. In another embodiment, R⁷ isazetidinyl.

In some embodiments of formula I or formula Ia, R¹⁰ is a carbocyclyl.For example, the carbocyclyl can be selected from the group consistingof cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certainembodiments, R¹⁰ is cyclopropyl. In another embodiment, R¹⁰ iscyclobutyl. In another embodiment, R¹⁰ is cyclopentyl. In anotherembodiment, R¹⁰ is cyclohexyl.

In some embodiments of formula I or formula Ia, R¹¹ is a heterocyclyl.For example, the heterocyclyl can be selected from the group consistingof morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, azetidinyland pyrrolidinyl. In certain embodiments, R¹¹ is morpholinyl. In anotherembodiment, R¹¹ is piperazinyl. In another embodiment, R¹¹ ispiperidinyl. In another embodiment, R¹¹ is pyrrolidinyl. In anotherembodiment, R¹¹ is azetidinyl.

In some embodiments of formula I or formula Ia, R¹¹ is a carbocyclyl.For example, the carbocyclyl can be selected from the group consistingof cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certainembodiments, R¹¹ is cyclopropyl. In another embodiment, R¹¹ iscyclobutyl. In another embodiment, R¹¹ is cyclopentyl. In anotherembodiment, R¹¹ is cyclohexyl.

In some embodiments of formula I or formula Ia, R¹² is a carbocyclyl.For example, the carbocyclyl can be selected from the group consistingof cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certainembodiments, R¹² is cyclopropyl. In another embodiment, R¹² iscyclobutyl. In another embodiment, R¹² is cyclopentyl. In anotherembodiment, R¹² is cyclohexyl.

In some embodiments of formula I or formula Ia, R¹³ is a heterocyclyl.For example, the heterocyclyl can be selected from the group consistingof morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, azetidinyland pyrrolidinyl. In certain embodiments, R¹³ is morpholinyl. In anotherembodiment, R¹³ is piperazinyl. In another embodiment, R¹³ ispiperidinyl. In another embodiment, R¹³ is pyrrolidinyl. In anotherembodiment, R¹³ is azetidinyl.

In some embodiments of formula I or formula Ia, R¹³ is a carbocyclyl.For example, the carbocyclyl can be selected from the group consistingof cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In certainembodiments, R¹³ is cyclopropyl. In another embodiment, R¹³ iscyclobutyl. In another embodiment, R¹³ is cyclopentyl. In anotherembodiment, R¹³ is cyclohexyl.

In some embodiments of formula I or formula Ia, R⁶ is one substituent.

In some embodiments of formula I or formula Ia, R⁶ is 1-2 substituents.

In some embodiments of formula I, R⁶ is 1-3 substituents.

In some embodiments of formula I, R⁶ is 1-4 substituents.

In some embodiments of formula I or formula Ia, R⁶ is H.

In some embodiments of formula I or formula Ia, R⁶ is one substituentand the substituent is a halide.

In some embodiments of formula I or formula Ia, R⁶ is one substituentand the substituent is —NH₂.

In some embodiments of formula I or formula Ia, R⁶ is one substituentand the substituent is —OCF₃.

In some embodiments of formula I or formula Ia, R⁶ is one substituentand the substituent is —OCH₃.

In some embodiments of formula I or formula Ia, R⁶ is one substituentand the substituent is —CF₃.

In some embodiments of formula I or formula Ia, R⁶ is one substituentand the substituent is -heterocyclylR⁸.

In some embodiments of formula I or formula Ia, R⁶ is one substituentand the substituent is —(CH₂)heterocyclylR⁸.

In some embodiments of formula I or formula Ia, R⁶ is one substituentand the substituent is —(CH₂)pyrrolidinylR⁸.

In some embodiments of formula I or formula Ia, R⁶ is one substituentand the substituent is —(CH₂)pyrrolidinylR⁸ where R⁸ is two substituentsand both substituents are halides.

In some embodiments of formula I or formula Ia, R⁶ is one substituentand the substituent is —(CH₂)piperidinylR⁸.

In some embodiments of formula I or formula Ia, R⁶ is one substituentand the substituent is —(CH₂)phenylR⁸.

In some embodiments of formula I or formula Ia, R⁶ is one substituentand the substituent is -phenoxyR⁸.

In some embodiments of formula I or formula Ia, R⁶ is one substituentand the substituent is

In some embodiments of formula I or formula Ia, R⁶ is one substituentand the substituent is —N(R¹⁰)₂.

In some embodiments of formula I or formula Ia, R⁶ is one substituentand the substituent is —N(R¹⁰)₂ where each R¹⁰ is independently selectedfrom C₁₋₃ alkyl.

In some embodiments of formula I or formula Ia, R⁶ is one substituentand the substituent is —(CH₂)N(R¹⁰)₂.

In some embodiments of formula I or formula Ia, R⁶ is one substituentand the substituent is —(CH₂)N(R¹⁰)₂ where each R¹⁰ is independentlyselected from C₁₋₃ alkyl.

In some embodiments of formula I or formula Ia, R⁶ is one substituentand the substituent is —N(R¹⁰)SO₂R¹¹.

In some embodiments of formula I or formula Ia, R⁶ is one substituentand the substituent is —N(R¹⁰)C(═O)R¹¹.

In some embodiments of formula I or formula Ia, R⁶ is one substituentand the substituent is —N(R¹⁰)C(═O)R¹¹ where R¹¹ is a heterocyclyl.

In some embodiments of formula I or formula Ia, R⁶ is one substituentand the substituent is —N(R¹⁰)C(═O)R¹¹ where R¹¹ is a carbocyclyl.

In some embodiments of formula I, R⁶ is two substituents and thesubstituents are fluorine and —(C₁₋₉ alkyl)_(n)heterocyclylR⁸.

In some embodiments of formula Ia, R⁶ is two substituents and thesubstituents are fluorine and -heterocyclylR⁸.

In some embodiments of formula Ia, R⁶ is two substituents and thesubstituents are fluorine and —(C₁₋₂ alkyl)heterocyclylR⁸.

In some embodiments of formula I or formula Ia, R⁶ is one substituentand the substituent is select from the group consisting of

In some embodiments of formula I or formula Ia, R⁷ is one substituent.

In some embodiments of formula I or formula Ia, R⁷ is 1-2 substituents.

In some embodiments of formula I, R⁷ is 1-3 substituents.

In some embodiments of formula I, R⁷ is 1-4 substituents.

In some embodiments of formula I or formula Ia, R⁷ is one substituentand the substituent is a halide.

In some embodiments of formula I or formula Ia, R⁷ is one substituentand the substituent is —NH₂.

In some embodiments of formula I or formula Ia, R⁷ is one substituentand the substituent is —OH.

In some embodiments of formula I or formula Ia, R⁷ is one substituentand the substituent is —CF₃.

In some embodiments of formula I or formula Ia, R⁷ is one substituentand the substituent is —CN.

In some embodiments of formula I, R⁷ is one substituent and thesubstituent is —XR¹⁰ where X is O and R¹⁰ is C₁₋₃ alkyl.

In some embodiments of formula Ia, R⁷ is one substituent and thesubstituent is —OR¹⁰ and R¹⁰ is C₁₋₃ alkyl.

In some embodiments of formula I or formula Ia, R⁷ is one substituentand the substituent is -phenylR⁹.

In some embodiments of formula I or formula Ia, R⁷ is one substituentand the substituent is —(CH₂)N(R¹⁰)₂.

In some embodiments of formula I or formula Ia, R⁷ is one substituentand the substituent is —(CH₂)N(R¹⁰)₂ where each R¹⁰ is independentlyselected from C₁₋₃ alkyl.

In some embodiments of formula I or formula Ia, R⁷ is one substituentand the substituent is —(CH₂)heterocyclylR⁹.

In some embodiments of formula I or formula Ia, R⁷ is one substituentand the substituent is —(CH₂)pyrrolidinylR⁹.

In some embodiments of formula I or formula Ia, R⁷ is one substituentand the substituent is -heterocyclylR⁹.

In some embodiments of formula I or formula Ia, R⁷ is one substituentand the substituent is -phenoxyR⁹.

In some embodiments of formula I or formula Ia, R⁷ is one substituentand the substituent is —(CH₂)phenylR⁹.

In some embodiments of formula I or formula Ia, R⁷ is one substituentand the substituent is -phenylR⁹.

In some embodiments of formula I or formula Ia, R⁷ is one substituentand the substituent is —N(R¹⁰)C(═O)R¹¹.

In some embodiments of formula I or formula Ia, R⁷ is one substituentand the substituent is —N(R¹⁰)C(═O)R¹¹ where R¹¹ is a carbocyclyl.

In some embodiments of formula I or formula Ia, R⁷ is one substituentand the substituent is —N(R¹⁰)₂.

In some embodiments of formula I or formula Ia, R⁷ is one substituentand the substituent is —C(═O)R¹¹ where R¹¹ is select from the groupconsisting of -heterocyclylR⁸ and —N(R¹⁰)₂.

In some embodiments of formula I or formula Ia, R⁷ is one substituentand the substituent is —SO₂R¹¹.

In some embodiments of formula I or formula Ia, R⁷ is one substituentand the substituent is —SO₂R¹¹; and R¹¹ is C₁₋₃ alkyl.

In some embodiments of formula I or formula Ia, R⁷ is two substituentsand the substituents are C₁₋₃ alkyl and -heterocyclylR⁹.

In some embodiments of formula I or formula Ia, R⁷ is one substituentand the substituent is select from the group consisting of

In some embodiments of formula I or formula Ia, R⁸ is one substituent.

In some embodiments of formula I or formula Ia, R⁸ is 1-2 substituents.

In some embodiments of formula I, R⁸ is 1-3 substituents.

In some embodiments of formula I, R⁸ is 1-4 substituents.

In some embodiments of formula I or formula Ia, R⁸ is H.

In some embodiments of formula I or formula Ia, R⁸ is one substituentand the substituent is C₁₋₃ alkyl.

In some embodiments of formula I or formula Ia, R⁸ is one substituentand the substituent is —OH.

In some embodiments of formula I or formula Ia, R⁸ is one substituentand the substituent is a halide.

In some embodiments of formula I or formula Ia, R⁸ is two substituentsand the substituents are halides.

In some embodiments of formula I, R⁸ is three substituents and thesubstituents are halides.

In some embodiments of formula I or formula Ia, R⁹ is one substituent.

In some embodiments of formula I or formula Ia, R⁹ is 1-2 substituents.

In some embodiments of formula I, R⁹ is 1-3 substituents.

In some embodiments of formula I, R⁹ is 1-4 substituents.

In some embodiments of formula I or formula Ia, R⁹ is H.

In some embodiments of formula I or formula Ia, R⁹ is one substituentand the substituent is C₁₋₃ alkyl.

In some embodiments of formula I or formula Ia, R⁹ is one substituentand the substituent is —OH.

In some embodiments of formula I or formula Ia, R⁹ is one substituentand the substituent is a halide.

In some embodiments of formula I or formula Ia, R⁹ is two substituentsand the substituents are halides.

In some embodiments of formula I or formula Ia, R⁸ is a —C₁₋₃ alkyl. Forexample, the —C₁₋₃ alkyl can be selected from the group consisting ofmethyl, ethyl, n-propyl and isopropyl. In certain embodiments, R⁸ ismethyl. In another embodiment, R⁸ is ethyl.

In some embodiments of formula I or formula Ia, R¹⁰ is a —C₁₋₃ alkyl.For example, the —C₁₋₃ alkyl can be selected from the group consistingof methyl, ethyl, n-propyl and iso-propyl. In certain embodiments, R¹⁰is methyl. In another embodiment, R¹⁰ is ethyl. In another embodiment,R¹⁰ is n-propyl. In another embodiment, R¹⁰ is iso-propyl.

In some embodiments of formula I or formula Ia, R¹¹ is a —C₁₋₃ alkyl.For example, the —C₁₋₃ alkyl can be selected from the group consistingof methyl, ethyl, n-propyl and iso-propyl. In certain embodiments, R¹¹is methyl. In another embodiment, R¹¹ is ethyl. In another embodiment,R¹¹ is n-propyl. In another embodiment, R¹¹ is iso-propyl.

In some embodiments of formula I or formula Ia, R¹⁴ is a —C₁₋₃ alkyl.For example, the —C₁₋₃ alkyl can be selected from the group consistingof methyl, ethyl, n-propyl and iso-propyl. In certain embodiments, R¹⁴is methyl. In another embodiment, R¹⁴ is ethyl. In another embodiment,R¹⁴ is n-propyl. In another embodiment, R¹⁴ is iso-propyl.

In some embodiments of formula I or formula Ia, R³ is -3-pyridylR⁶ andR⁵ is -3-pyridylR⁷; R⁶ is one substituent consisting of —(C₁₋₂alkyl)N(R¹⁰)₂; and R⁷ is one substituent consisting of —CF₃; and eachR¹⁰ is —C₁₋₃ alkyl.

In some embodiments of formula I or formula Ia, R³ is -3-pyridylR⁶ andR⁵ is -3-pyridylR⁷; R⁶ is one substituent consisting of —(C₁₋₂alkyl)heterocyclylR⁸; R⁷ and R⁸ are both H; and the heterocycle is a5-member ring.

In some embodiments of formula I or formula Ia, R³ is -3-pyridylR⁶ andR⁵ is -3-pyridylR⁷; R⁶ is one substituent consisting of —(C₁₋₂alkyl)heterocyclylR⁸; R⁷ and R⁸ are both H; and the heterocycle is a6-member ring.

In some embodiments of formula I or formula Ia, R³ is -3-pyridylR⁶ andR⁵ is -3-pyridylR⁷; R⁶ is one substituent consisting of —(C₁₋₂alkyl)heterocyclylR⁸; R⁷ is one substituent consisting of CN; R⁸ is H;and the heterocycle is a 5-member ring.

In some embodiments of formula I or formula Ia, R³ is -3-pyridylR⁶ andR⁵ is -3-pyridylR⁷; R⁶ is one substituent consisting of —(C₁₋₂alkyl)heterocyclylR⁸; R⁷ is one substituent consisting of CN; R⁸ is H;and the heterocycle is a 6-member ring.

In some embodiments of formula I or formula Ia, R³ is -3-pyridylR⁶ andR⁵ is -3-pyridylR⁷; R⁶ is one substituent consisting of —(C₁₋₂alkyl)heterocyclylR⁸; R⁷ is one substituent consisting of CF₃; R⁸ is H;and the heterocycle is a 6-member ring.

In some embodiments of formula I or formula Ia, R³ is -3-pyridylR⁶ andR⁵ is -3-pyridylR⁷; R⁶ is one substituent consisting of —(C₁₋₂alkyl)heterocyclylR⁸; R⁷ is one substituent consisting of-heterocyclylR⁸; each R⁸ is H; and the heterocycles are independentlyselected from a 5 or 6-member ring.

In some embodiments of formula I or formula Ia, R³ is -3-pyridylR⁶ andR⁵ is -3-pyridylR⁷; R⁶ is one substituent consisting of —(C₁₋₂alkyl)N(R¹⁰)₂; and R⁷ is one substituent consisting of —CN; and each R¹⁰is —C₁₋₃ alkyl.

In some embodiments of formula I or formula Ia, R³ is -3-pyridylR⁶ andR⁵ is -3-pyridylR⁷; R⁶ is one substituent consisting of —(C₁₋₂alkyl)N(R¹⁰)₂; and R⁷ is one substituent consisting of —(C₁₋₂alkyl)heterocyclylR⁸; R⁸ is H; each R¹⁰ is —C₁₋₃ alkyl; and theheterocycle is a 6-member ring.

In some embodiments of formula I or formula Ia, R³ is -3-pyridylR⁶ andR⁵ is -3-pyridylR⁷; R⁶ is one substituent consisting of —(C₁₋₂alkyl)heterocyclylR⁸; R⁷ is one substituent consisting of-heterocyclylR⁸; each R⁸ is one substituent independently selected fromH and —OH; and the heterocycles are independently selected from a 5 or6-member ring.

In some embodiments of formula I or formula Ia, R³ is -3-pyridylR⁶ andR⁵ is -3-pyridylR⁷; R⁶ is one substituent consisting of —(C₁₋₂alkyl)heterocyclylR⁸; R⁷ is one substituent consisting of —C(═O)R¹¹; R¹¹is -heterocyclylR⁸; each R⁸ is H; and the heterocycles are independentlyselected from a 5 or 6-member ring.

In some embodiments of formula I or formula Ia, R³ is -3-pyridylR⁶ andR⁵ is -3-pyridylR⁷; R⁶ is one substituent consisting of —(C₁₋₂alkyl)heterocyclylR⁸; R⁷ is one substituent consisting of-heterocyclylR⁸; each R⁸ is 1-3 substituents independently selected fromH and F with the proviso that at least one substituent on oneheterocycle is fluorine; and each heterocycle is a 5-member ring.

In some embodiments of formula I or formula Ia, R³ is -3-pyridylR⁶ andR⁵ is -3-pyridylR⁷; R⁶ is one substituent consisting of —(C₁₋₂alkyl)heterocyclylR⁸; R⁷ is one substituent consisting of —C(═O)R¹¹; R¹¹is —NHR¹⁰; R¹⁰ is heterocyclylR⁸; each R⁸ is H; and the heterocycles areindependently selected from a 5 or 6-member ring.

In some embodiments of formula I or formula Ia, R³ is -3-pyridylR⁶ andR⁵ is -3-pyridylR⁷; R⁶ is one substituent consisting of —(C₁₋₂alkyl)heterocyclylR⁸; R⁷ is one substituent consisting of —SO₂R¹¹; R⁸ isH; R¹¹ is —C₁₋₃ alkyl; and the heterocycle is a 6-member ring.

In some embodiments of formula I or formula Ia, R³ is -3-pyridylR⁶ andR⁵ is -3-pyridylR⁷; R⁶ is one substituent consisting of —(C₁₋₂alkyl)heterocyclylR⁸; R⁷ is H; R⁸ is 1-4 substituents independentlyselected from H and F with the proviso that at least one substituent isfluorine; and the heterocycle is a 5-member ring.

Illustrative compounds of Formula (I) are shown in Table 1.

TABLE 1

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384

385

386

387

388

389

390

391

392

393

394

395

396

397

398

399

400

401

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

433

434

435

436

437

438

439

440

441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

466

467

468

469

470

471

472

473

474

475

476

477

478

479

480

481

482

483

484

485

486

487

488

489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

505

506

507

508

509

510

511

512

513

514

515

516

517

518

519

520

521

522

523

524

525

526

527

528

529

530

531

532

533

534

535

536

537

538

539

540

541

542

543

544

545

546

547

548

549

550

551

552

553

554

555

556

557

558

559

560

561

562

563

564

565

566

567

568

569

570

571

572

573

574

575

576

577

578

579

580

581

582

583

584

585

586

587

588

589

590

591

592

593

594

595

596

597

598

599

600

601

602

603

604

605

606

607

608

609

610

611

612

613

614

615

616

617

618

619

620

621

622

623

624

625

626

627

628

629

630

631

632

633

634

635

636

637

638

639

640

641

642

643

644

645

646

647

648

649

650

651

652

653

654

655

656

657

658

659

660

661

662

663

664

665

666

667

668

669

670

671

672

673

674

675

676

677

678

679

680

681

682

683

684

685

686

687

688

689

690

691

692

693

694

695

696

697

698

699

700

701

702

703

704

705

706

707

708

709

710

711

712

713

714

715

716

717

718

719

720

721

722

723

724

725

726

727

728

729

730

731

732

733

734

735

736

737

738

739

740

741

742

743

744

745

746

747

748

749

750

751

752

753

754

755

756

757

758

759

760

761

762

763

764

765

766

767

768

769

770

771

772

773

774

775

776

777

778

779

780

781

782

783

784

785

786

787

788

789

790

791

792

793

794

795

796

797

798

799

800

801

802

803

804

805

806

807

808

809

810

811

812

813

814

815

816

817

818

819

820

821

822

823

824

825

826

827

828

829

830

831

832

833

834

835

836

837

838

839

840

841

842

843

844

845

846

847

848

849

850

Compound Preparation

The starting materials used in preparing the compounds of the inventionare known, made by known methods, or are commercially available. It willbe apparent to the skilled artisan that methods for preparing precursorsand functionality related to the compounds claimed herein are generallydescribed in the literature. The skilled artisan given the literatureand this disclosure is well equipped to prepare any of the compounds.

It is recognized that the skilled artisan in the art of organicchemistry can readily carry out manipulations without further direction,that is, it is well within the scope and practice of the skilled artisanto carry out these manipulations. These include reduction of carbonylcompounds to their corresponding alcohols, oxidations, acylations,aromatic substitutions, both electrophilic and nucleophilic,etherifications, esterification and saponification and the like. Thesemanipulations are discussed in standard texts such as March's AdvancedOrganic Chemistry; Reactions, Mechanisms, and Structure 6^(th) Ed., JohnWiley & Sons (2007), Carey and Sundberg, Advanced Organic Chemistry5^(th) Ed., Springer (2007), Comprehensive Organic Transformations; AGuide to Functional Group Transformations, 2^(nd) Ed., John Wiley & Sons(1999) (incorporated herein by reference in its entirety) and the like.

The skilled artisan will readily appreciate that certain reactions arebest carried out when other functionality is masked or protected in themolecule, thus avoiding any undesirable side reactions and/or increasingthe yield of the reaction. Often the skilled artisan utilizes protectinggroups to accomplish such increased yields or to avoid the undesiredreactions. These reactions are found in the literature and are also wellwithin the scope of the skilled artisan. Examples of many of thesemanipulations can be found for example in T. Greene and P. WutsProtecting Groups in Organic Synthesis, 4th Ed., John Wiley & Sons(2007), incorporated herein by reference in its entirety.

To further illustrate this invention, the following examples areincluded. The examples should not, of course, be construed asspecifically limiting the invention. Variations of these examples withinthe scope of the claims are within the purview of one skilled in the artand are considered to fall within the scope of the invention asdescribed, and claimed herein. The reader will recognize that theskilled artisan, armed with the present disclosure, and skill in the artis able to prepare and use the invention without exhaustive examples.

Trademarks used herein are examples only and reflect illustrativematerials used at the time of the invention. The skilled artisan willrecognize that variations in lot, manufacturing processes, and the like,are expected. Hence the examples, and the trademarks used in them arenon-limiting, and they are not intended to be limiting, but are merelyan illustration of how a skilled artisan may choose to perform one ormore of the embodiments of the invention.

(¹H) nuclear magnetic resonance spectra (NMR) were measured in theindicated solvents on a Bruker NMR spectrometer (Avance™ DRX300, 300 MHzfor ¹H or Avance™ DRX500, 500 MHz for ¹H) or Varian NMR spectrometer(Mercury 400BB, 400 MHz for ¹H). Peak positions are expressed in partsper million (ppm) downfield from tetramethylsilane. The peakmultiplicities are denoted as follows, s, singlet; d, doublet; t,triplet; q, quartet; ABq, AB quartet; quin, quintet; sex, sextet; sep,septet; non, nonet; dd, doublet of doublets; d/ABq, doublet of ABquartet; dt, doublet of triplets; td, triplet of doublets; m, multiplet.

The following abbreviations have the indicated meanings:

-   -   brine=saturated aqueous sodium chloride    -   CDCl₃=deuterated chloroform    -   DCE=dichloroethane    -   DCM=dichloromethane    -   DHP=dihydropyran    -   DIPEA=diisopropylethylamine    -   DMF=N,N-dimethylformamide    -   DMSO-d₆=deuterated dimethylsulfoxide    -   ESIMS=electron spray mass spectrometry    -   EtOAc=ethyl acetate    -   EtOH=ethanol    -   h=hour    -   HATU=2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium        hexafluorophosphate    -   HCl=hydrochloric acid    -   HOAc=acetic acid    -   H₂SO₄=sulfuric acid    -   iPrOH=iso-propyl alcohol    -   KOAc=potassium acetate    -   K₃PO₄=potassium phosphate    -   LAH=lithium aluminum hydride    -   mCPBA=meta-Chloroperoxybenzoic acid    -   MeOH=methanol    -   MgSO₄=magnesium sulfate    -   min.=minute    -   MW=microwave    -   NaBH(OAc)₃=sodium triacetoxyborohydride    -   NaHCO₃=sodium bicarbonate    -   NaHSO₃=sodium bisulfite    -   NaHSO₄=sodium bisulfate    -   NaOH=sodium hydroxide    -   NH₄OH=ammonium hydroxide    -   NMR=nuclear magnetic resonance    -   Pd/C=palladium(O) on carbon    -   PdCl₂(dppf)₂=1,1′-bis(diphenylphosphino)ferrocene]palladium(II)        chloride    -   Pd₂(dba)₃=tris(dibenzylideneacetone)dipalladium(O)    -   Pd(PPh₃)₄=tetrakis(triphenylphosphine)palladium(O)    -   PPTS=pyridinium p-toluenesulfonate    -   r.t.=room temperature    -   sat^(d).=saturated    -   sol^(n).=solution    -   Reflx.=heated to reflux    -   TEA=triethylamine    -   TFA=trifluoroacetic acid    -   THF=tetrahydrofuran    -   TLC=thin layer chromatography    -   Tr-Cl=trityl chloride or triphenylmethyl chloride

The following example schemes are provided for the guidance of thereader, and collectively represent an example method for making thecompounds provided herein. Furthermore, other methods for preparingcompounds of the invention will be readily apparent to the person ofordinary skill in the art in light of the following reaction schemes andexamples. The skilled artisan is thoroughly equipped to prepare thesecompounds by those methods given the literature and this disclosure. Thecompound numberings used in the synthetic schemes depicted below aremeant for those specific schemes only, and should not be construed as orconfused with same numberings in other sections of the application.Unless otherwise indicated, all variables are as defined above.

General Procedures

Compounds of Formula I of the present invention can be prepared asdepicted in Scheme 1.

Scheme 1 describes a method for preparation of indazole-3-carboxamidederivatives (I) by first forming the Weinreb amide (III) of a1H-indazole-3-carboxylic acid (II). The Weinreb amide (III) is reactedwith (bis(trifluoroacetoxy)iodo)benzene to produce the5-iodo-1H-indazole-3-carboxylic acid (IV) followed by THP protection ofthe indazole nitrogen. The Weinreb amide of protected indazole V isreduced to aldehyde VI followed by reaction with bis(pinacolato)diboronto give the pinacol ester (VII). Suzuki coupling with a variety ofaromatic and nonaromatic bromides yields the R³ substituted indazoleVIII. Oxidation of the aldehyde to the acid (IX) followed by HATUmediated coupling of a variety of amines and sequent deprotectionproduces the desired indazole-3-carboxamide derivatives (I).

Compounds of Formula I of the present invention can also be prepared asdepicted in Scheme 2.

Scheme 2 describes an alternative method for preparation ofindazole-3-carboxamide derivatives (I) by bromination of the indazole5-position followed by esterification to form ester XII. The indazolenitrogen is THP protected and the ester is hydrolyzed to acid XIV. Theacid is coupled with a variety of amines to produce amide XV which isthen coupled with a variety of boronic acids (Route 1) to give X.Alternatively, XV can be converted to the boronate ester and then coupleto a variety of bromides (Route 2) to yield X. Final deprotection of theindazole nitrogen yields the desired indazole-3-carboxamide derivatives(I).

Compounds of Formula I of the present invention can also be prepared asdepicted in Scheme 3.

Scheme 3 describes another alternative method for preparation ofindazole-3-carboxamide derivatives (I) by bromination of the indazole5-position followed by either Route 1: esterification to form ester XII,then trityl protection of the indazole nitrogen and then finallyhydrolyzed of the ester to acid XVII; or Route 2: trityl protection ofthe indazole nitrogen directly to acid XVII. The acid is coupled with avariety of amines to produce amide XVIII which is then coupled with avariety of boronic acids (Route 3) to give XIX. Alternatively, XVIII canbe converted to the boronate ester and then couple to a variety ofbromides (Route 4) to yield XIX. Final deprotection of the indazolenitrogen yields the desired indazole-3-carboxamide derivatives (I).

ILLUSTRATIVE COMPOUND EXAMPLES

Preparation of intermediate 3-(5-bromopyridin-3-yl)-1,1-dimethylurea(XXII) is depicted below in Scheme 4.

Step 1

3-Amino-5-bromo pyridine (XX) (1.0 g, 5.78 mmol) was dissolved inpyridine and cooled to 0° C. before adding dimethyl carbamyl chloride(XXI) (0.683 g, 6.35 mmol). The reaction mixture was stirred at roomtemperature for 2 h and then heated overnight at 60° C. under argon. Thesolution was cooled to room temperature, poured into ice water andextracted with EtOAc. The organic extract was dried over MgSO₄, filteredand concentrated to a residue to afford3-(5-bromopyridin-3-yl)-1,1-dimethylurea (XXII) as a brown solid, (1.24g, 5.09 mmol, 88% yield). ¹H NMR (DMSO-d₆) δ ppm 8.67-8.64 (m, 2H), 8.23(d, J=7.8 Hz, 1H), 2.93 (s, 6H); ESIMS found for C₈H₁₀BrN₃O m/z 245.05(M+H).

The following intermediates were prepared in accordance with theprocedure described in the above Scheme 4.

N-(5-bromopyridin-3-yl)morpholine-4-carboxamide (XXIII): Tan solid (0.82g, 48%). ¹H NMR (DMSO-d₆) 3.43-3.45 (m, 4H), 3.60-3.62 (m, 4H), 8.21 (t,J=2.0 Hz, 1H), 8.26 (d, J=2.0 Hz, 1H), 8.62 (d, J=2.2 Hz, 1H), 8.91 (s,1H); ESIMS found for C₁₀H₁₂BrN₃O₂ m/z 286 (M+H).

N-(5-bromopyridin-3-yl)cyclopropanecarboxamide (XXIV): Off white solid,(83% yield), ¹H NMR (CDCl₃, 400 MHz) δ ppm 8.46-8.39 (m, 3H), 7.54 (bs,1H), 1.56-1.50 (m, 1H), 1.13-1.07 (m, 2H), 0.96-0.90 (m, 2H); ESIMSfound for C₉H₉BrN₂O m/z 240.85 (M+H).

Preparation of intermediate (XXVI) is depicted below in Scheme 5.

Step 1

To a solution of 5-bromonicotinaldehyde (XXV) (5.0 g, 26.9 mmol) in DCE(108 mL) was added dimethylamine-HCl (4.39 g, 53.8 mmol) and TEA (7.5 g,53.8 mmol). The reaction was stirred at room temperature for 1 h.NaBH(OAc)₃ was added and the reaction was stirred overnight at roomtemperature. The reaction was diluted with DCM and sat. aq. NaHCO₃. Theorganic layer was separated, washed with water, brine, dried andconcentrated under vacuum to produce1-(5-bromopyridin-3-yl)-N,N-dimethylmethanamine (XXVI) as a brown liquid(92.6% yield). ¹H NMR (CDCl₃) δ ppm 2.15 (s, 6H), 3.43 (s, 2H), 7.94 (s,1H), 8.47 (d, J=2 Hz, 1H), 8.59 (d, J=3 Hz, 1H); ESIMS found forC₈H₁₁BrN₂ m/z 215 (M^(Br79)+H) and 217 (M^(Br81)+H).

The following intermediates were prepared in accordance with theprocedure described in the above Scheme 5.

3-Bromo-5-(pyrrolidin-1-ylmethyl)pyridine (XXVII): Golden liquid (1.35g, 97% yield). ¹H NMR (DMSO-d₆) 1.68-1.71 (m, 4H), 2.42-2.44 (m, 4H),3.60 (s, 2H), 7.96 (s, 1H), 8.48 (d, J=2 Hz, 1H), 8.58 (d, J=3 Hz, 1H);ESIMS found for C₁₀H₁₃BrN₂ m/z 242 (M+H).

3-Bromo-5-(piperidin-1-ylmethyl)pyridine (XXVIII): Brown liquid (13.1 g,94% yield). ¹H NMR (DMSO-d₆) 1.36-1.39 (m, 2H), 1.46-1.51 (m, 4H),2.31-2.32 (m, 4H), 3.46 (s, 2H), 7.94 (s, 1H), 8.47 (d, J=2 Hz, 1H),8.58 (d, J=3 Hz, 1H); ESIMS found for C₁₁H₁₅BrN₂ m/z 257 (M+H).

4-((5-Bromopyridin-3-yl)methyl)morpholine (XXIX): Brown oil (1.02 g,35.6% yield). ESIMS found for C₁₀H₁₃BrN₂O m/z 258 (M+H).

1-((5-Bromopyridin-3-yl)methyl)-4-methylpiperazine (XXX): Brown oil(0.93 g, 64% yield). ¹H NMR (DMSO-d₆) 2.14 (s, 3H), 2.27-2.37 (m, 8H),3.49 (s, 2H), 7.95 (s, 1H), 8.47 (d, J=1.7 Hz, 1H), 8.59 (d, J=2.2 Hz,1H); ESIMS found for C₁₁H₁₆BrN₃ m/z 272 (M+H).

1-(3-Bromo-5-fluorobenzyl)-4-methylpiperazine (XXXI): Light yellow oil(2.07 g, 68% yield). ¹H NMR (DMSO-d₆) 2.14 (s, 3H), 2.28-2.40 (m, 8H),3.46 (s, 2H), 7.15-7.17 (m, 1H), 7.35 (s, 1H), 7.40-7.42 (m, 1H); ESIMSfound for C₁₂H₁₆BrFN₂ m/z 288 (M+H).

1-(5-Bromopyridin-3-yl)piperidin-4-ol (XXXII): Brown oil (2.15 g, 7.93mmol, 72.7% yield). ¹H NMR (DMSO-d₆) 1.34-1.41 (m, 2H), 1.67-1.71 (m,2H), 2.03-2.07 (m, 2H), 2.62-2.64 (m, 2H), 3.42-3.46 (m, 1H), 3.47 (s,2H), 4.55 (d, J=4.2 Hz, 1H), 7.93-7.94 (m, 1H), 8.46 (d, J=1.6 Hz, 1H),8.58 (d, J=2.2 Hz, 1H); ESIMS found for C₁₁H₁₅BrN₂O m/z 272 (M+H).

3-Bromo-5-((3,3-difluoropyrrolidin-1-yl)methyl)pyridine (XXXIII): Brownliquid (7.38 g, 26.64 mmol, 94.9% yield). ¹H NMR (DMSO-d₆) 2.21-2.30 (m,2H), 2.70 (t, J=7 Hz, 2H), 2.89 (t, J=13 Hz, 2H), 3.66 (s, 2H),7.95-7.98 (m, 1H), 8.57 (d, J=1.7 Hz, 1H), 8.61 (d, J=2.2 Hz, 1H); ESIMSfound for C₁₀H₁₁BrF₂N₂ m/z 276 (M+H).

Preparation of 3-benzyl-5-bromopyridine (XXXVI) is depicted below inScheme 6.

Step 1

To a solution of 3,5-dibromopyridine (XXXIV) (1.03 g, 4.36 mmol) in THF(7 mL) under argon was added CuI (50 mg, 0.26 mmol) and PdCl₂(dppf)₂(178 mg, 0.22 mmol). Benzylzinc(II) bromide (XXXV) (0.5M in THF) (13.09mL, 6.55 mmol) was slowly added by syringe. The reaction was heated at50° C. over the weekend. The reaction was quenched with water andextracted with EtOAc. The EtOAc was separated, washed with water, brine,dried over MgSO₄ and concentrated under vacuum. The residue was purifiedon a silica gel column (100% hexanes→5:95 EtOAc:hexanes) to afford3-benzyl-5-bromopyridine (XXXVI) (0.614 g, 2.47 mmol, 57% yield) as alight brown oil. ¹H NMR (DMSO-d₆) δ ppm 3.98 (s, 2H), 7.19-7.23 (m, 1H),7.27-7.32 (m, 4H), 7.92-7.93 (m, 1H), 8.51 (d, J=2 Hz, 1H), 8.54 (d, J=3Hz, 1H); ESIMS found for C₁₂H₁₀BrN m/z 248 (M+H).

Preparation of 3-bromo-5-phenoxypyridine (XXXIX) is depicted below inScheme 7.

Step 1

To a solution of 3,5-dibromopyridine (XXXVII) (1.00 g, 4.24 mmol) in NMP(11 mL) was added phenol (XXXVIII) (398 mg, 4.24 mmol) and CsCO₃ (1.38g, 4.24 mmol). The reaction was heated at 100° C. over the weekend. Thereaction was then partitioned between Et₂O/water. The Et₂O wasseparated, washed with 2× water, brine, dried over MgSO₄ andconcentrated under vacuum. The residue was purified on a silica gelcolumn (100% hexanes→2:98 EtOAc:hexanes) to afford3-bromo-5-phenoxypyridine (XXXIX) (535 mg, 2.14 mmol, 50% yield) as aclear oil. ¹H NMR (DMSO-d₆) δ ppm 7.13-7.15 (m, 2H), 7.23-7.26 (m, 1H),7.43-7.46 (m, 2H), 7.69-7.70 (m, 1H), 8.37 (d, J=3 Hz, 1H), 8.49 (d, J=2Hz, 1H); ESMS found for C₁₁H₈BrNO m/z 250 (M+H).

Preparation of 1-(5-bromopyridin-3-yl)-4-methylpiperazine (XL) isdepicted below in Scheme 8.

Step 1

To a solution of 3,5-dibromopyridine (XXXVIII) (2.90 g, 12.24 mmol) indry DMF (20 mL) was added 1-methylpiperazine (2.987 mL, 26.93 mmol) andK₂CO₃ (5.58 g, 40.39 mmol). The reaction was heated at 120° C.overnight. An additional portion of 1-methylpiperazine (6 mL) was addedand heating was continued for another 24 h. The reaction was poured intoice water and filtered. The filtrate was extracted with 66% MeOH/CHCl₃.The organic layer was dried over MgSO4, filtered and concentrated undervacuum to yield 1-(5-bromopyridin-3-yl)-4-methylpiperazine (XL) as abrown viscous oil (2.49 g, 9.76 mmol, 79.8% yield). ESIMS found forC₁₀H₁₄BrN₃ m/z 256 (M+H).

The following intermediate was prepared in accordance with the proceduredescribed in the above Scheme 8.

4-(5-Bromopyridin-3-yl)morpholine (XLI): Yellow solid (1.12 g, 4.61mmol, 64.9% yield). ESIMS found for C₉H₁₁BrN₂O m/z 244.1 (M+H).

Preparation of 5-bromo-N-cyclohexylnicotinamide (XLIV) is depicted belowin Scheme 9.

Step 1

To a solution of 5-bromonicotinic acid (XLII) (500 mg, 2.49 mmol) in DMF(8 mL) was added cyclohexanamine (XLIII) (247 mg, 2.49 mmol) and DIPEA(643 mg, 4.98 mmol). The reaction was cooled at 0° C. before adding HATU(947 mg, 2.49 mmol). The reaction was warmed to room temperature andstirred for 4 hrs. The reaction was diluted with EtOAc, washed with 2×water, brine, dried over MgSO₄ and concentrated under vacuum to yieldcrude 5-bromo-N-cyclohexylnicotinamide (XLIV). The product was usedwithout further purification. ESIMS found for C₁₁H₁₅BrN₂O m/z 283 (M+H).

Preparation of3-bromo-5-(((2R,6S)-2,6-dimethylpiperidin-1-yl)methyl)pyridine (XLVII)is depicted below in Scheme 10.

Step 1

To a solution of 5-bromonicotinaldehyde (XXV) (2.05 g, 11.0 mmol) inMeOH (85 mL) was added NaBH₄ (832 mg, 21.99 mmol). The reaction wasstirred at room temperature for 1 h. The reaction was quenched withsaturated aqueous NH₄Cl (5 mL). The reaction was concentrated undervacuum and the residue was partitioned between saturated aqueousNH₄Cl/EtOAc. The organic layer was separated, washed with water, brine,dried over MgSO₄ and concentrated under vacuum to yield crude(5-bromopyridin-3-yl)methanol (XLV) as a golden oil (1.54 g, 8.2 mmol,74% yield). The product was used without further purification. ESIMSfound for C₆H₆BrNO m/z 188 (M+H).

Step 2

(5-Bromopyridin-3-yl)methanol (XLV) (1.54 g, 8.2 mmol) was treated with4M HCl in dioxane (10 mL) at 0° C. and then evaporated. The residue wasdissolved in SOCl₂ (4 mL) and refluxed for 2 hrs. The SOCl₂ was removedand the residue was triturated with hexane to produce HCl salt of3-bromo-5-(chloromethyl)pyridine (XLVI) as a brown solid (1.30 g, 5.4mmol, 66% yield). The product was used without further purification.ESIMS found for C₆H₅BrClN m/z 206 (M+H).

Step 3

To a solution of 3-bromo-5-(chloromethyl)pyridine (XLVI) (1.17 g, 4.8mmol) in MeCN (0.2 mL) and (2S,6R)-2,6-dimethylpiperidine (2.6 mL, 19.3mmol) was added K₂CO₃ (667 mg, 4.8 mmol). The reaction was refluxed for5 hrs. TLC showed the presence of starting material so additional(2S,6R)-2,6-dimethylpiperidine (2.0 mL, 14.8 mmol) was added and thereaction was refluxed for an additional 5 hrs. The solvent was removedand the residue was partitioned between EtOAc/water. The EtOAc wasseparated and washed with brine, dried over MgSO₄ and concentrated undervacuum. The residue was purified on a silica gel column (100%hexanes→6:94 EtOAc:hexanes) to afford3-bromo-5-(((2R,6S)-2,6-dimethylpiperidin-1-yl)methyl)pyridine (XLVII)as a clear oil (728 mg, 2.57 mmol, 53% yield). ¹H NMR (DMSO-d₆) δ ppm0.92 (d, J=8 Hz, 6H), 1.21-1.32 (m, 3H), 1.52-1.55 (m, 2H), 1.59-1.63(m, 1H), 2.42-2.46 (m, 2H), 3.73 (s, 2H), 7.97-7.98 (m, 1H), 8.50 (d,J=3 Hz, 1H), 8.55-8.56 (m, 1H); ESIMS found for C₁₃H₁₉BrN₂ m/z 283(M+H).

Preparation of intermediate 3′-fluorobiphenyl-3-amine (LI) is depictedbelow in Scheme 11.

Step 1

A 25 mL microwave vessel was charged with 1-bromo-3-nitrobenzene(XLVIII) (0.61 g, 3.0 mmol), 3-fluorophenylboronic acid (XLIX) (0.46 g,3.3 mmol), potassium phosphate tribasic (0.95 g, 4.5 mmol), 1,4-dioxane(15.0 mL), and water (3.0 mL). Tetrakis(triphenylphosphine)palladium(O)(0.17 g, 0.15 mmol) was added, and the reaction was placed in amicrowave reactor for 1 h at 95° C. An additional 3-fluorophenylboronicacid (0.20 g) and tetrakis(triphenylphosphine)palladium(O) (0.05 g) wereadded, and the reaction was heated for another 1 h at 95° C. in amicrowave reactor. The organic solvent was separated from the water andconcentrated to a residue. The residue was then purified by flashchromatography using a 25 g Thomson normal phase silica gel cartridge(100% hexanes→1:99 EtOAc:hexanes) to afford 3′-fluoro-3-nitrobiphenyl(L) (0.63 g, 2.91 mmol, 97% yield) as a white solid. ¹H NMR (DMSO-d₆) δppm 8.48 (t, J=2.0 Hz, 1H), 8.26-8.24 (m, 1H), 8.20-8.18 (m, 1H), 7.78(t, J=8 Hz, 1H), 7.70-7.68 (m, 1H), 7.67-7.65 (m, 1H), 7.59-7.56 (m,1H), 7.32-7.28 (m, 1H).

Step 2

10% Palladium on carbon (0.095 g) was added to a solution of3′-fluoro-3-nitrobiphenyl (L) (0.63 g, 2.88 mmol) in EtOH (20.0 mL). Theflask was evacuated and replaced with a hydrogen atmosphere. Thesolution was stirred at room temperature for 5 h under hydrogen. Thecatalyst was filtered through a pad of Celite, and the solvent wasremoved under reduced pressure. The residue was purified by flashchromatography using a 40 g Thomson normal phase silica gel cartridge(100% hexanes→15:85 EtOAc:hexanes) to afford 3′-fluorobiphenyl-3-amine(LI) (0.34 g, 1.81 mmol, 63% yield) as a light yellow oil. ¹H NMR(DMSO-d₆) δ ppm 7.47-7.44 (m, 1H), 7.40-7.39 (m, 1H), 7.36-7.33 (m, 1H),7.15-7.14 (m, 1H), 7.10 (t, J=7.7 Hz, 1H), 6.85-6.84 (m, 1H), 6.80-6.79(m, 1H), 6.60-6.58 (m, 1H), 5.18 (s, 2H); ESIMS found for C₁₂H₁₀FN m/z188 (M+H).

Preparation of intermediate 5-(3-fluorophenyl)pyridin-3-amine (LIII) isdepicted below in Scheme 12.

Step 1

To a microwave vial was added 3-amino-5-bromopyridine (LII) (0.400 g,2.31 mmol), 3-fluorophenyl boronic acid (XLIX) (0.356 g, 2.54 mmol),tetrakis(triphenylphosphine)palladium(O) (0.133 g, 0.116 mmol),potassium phosphate (0.736 g, 3.47 mmol), water (1 mL), and DMF (5 mL).The reaction vial was capped, purged with argon and heated undermicrowave irradiation for 1 h at 180° C. The solution was filteredthrough a pad of Celite and concentrated under vacuum. The residue waspurified by column chromatography (4:6 EtOAc:hexanes→7:3 EtOAc:hexanes)to afford the 5-(3-fluorophenyl)pyridin-3-amine (LIII) (0.360 g, 1.92mmol, 83% yield) as a yellow-white solid. ESIMS found for C₁₁H₉FN₂ m/z189.1 (M+H).

Preparation of intermediate 5-((dimethylamino)methyl)pyridin-3-amine(LVII) is depicted below in Scheme 13.

Step 1

5-Bromonicontinaldehyde (XXV) (5.01 g, 26.9 mmol) and dimethylaminehydrochloride (4.39 g, 53.8 mmol) were suspended in 1,2-dichloroethane(108 mL). Triethylamine (7.50 mL, 53.8 mmol) was added, and the reactionwas stirred at room temperature for 1 h. Sodium triacetoxyborohydride(8.56 g, 40.4 mmol) was added, and the reaction was further stirred atroom temperature overnight. The reaction was diluted with saturatedsodium bicarbonate solution and DCM. The organic layer was separated,washed sequentially with water and brine, dried over MgSO₄, filtered andconcentrated to give 1-(5-bromopyridin-3-yl)-N,N-dimethylmethanamine(LIV) (1.19 g, 23.9 mmol, 89% yield) as a brown oil: ¹H NMR (DMSO-d₆) δppm 8.59 (d, J=3 Hz, 1H), 8.47 (d, J=2 Hz, 1H), 7.94 (s, 1H), 3.43 (s,2H), 2.15 (s, 6H); ESIMS found for C₈H₁₁BrN₂ m/z 215 (M+H).

Step 2

In a 25 mL microwave vessel,1-(5-bromopyridin-3-yl)-N,N-dimethylmethanamine (LIV) (1.27 g, 5.92mmol), 4-methoxybenzylamine (LV) (0.77 mL, 5.92 mmol), cesium carbonate(2.70 g, 8.29 mmol) and xanthphos (0.17 g, 0.30 mmol) were suspended inxylenes (12.0 mL). The solvent was degassed, andtris(dibenzylideneacetone)dipalladium(O) (0.27 g, 0.30 mmol) was added.The vessel was sealed, and the reaction was heated to 130° C. for 5 h ina microwave reactor. The solvent was decanted away from the solidmaterial and concentrated to a residue. The residue was purified bysilica gel chromatography using a 40 g Thomson normal-phase silica gelcartridge (100% CHCl₃→3:97 MeOH[7N Mb]:CHCl₃) to afford5-((dimethylamino)methyl)-N-(4-methoxybenzyl)pyridin-3-amine (LVI) (0.68g, 2.49 mmol, 42% yield) as a yellow solid. ¹H NMR (DMSO-d₆) δ ppm 7.84(d, J=3 Hz, 1H), 7.64 (d, J=2 Hz, 1H), 7.27 (d, J=1 Hz, 2H), 6.88 (d,J=1 Hz, 2H), 6.83-6.82 (m, 1H), 6.35 (t, J=8 Hz, 1H), 4.20 (d, J=8 Hz,2H), 3.72 (s, 3H), 3.24 (s, 2H), 2.08 (s, 6H); ESIMS found for C₁₆H₂₁N₃Om/z 272 (M+H).

Step 3

5-((dimethylamino)methyl)-N-(4-methoxybenzyl)pyridin-3-amine (LVI) (0.15g, 0.56 mmol) was dissolved in TFA (2.0 mL) and stirred at roomtemperature for 1 h. The TFA was removed, and the residue was treatedwith 7N ammonia in MeOH/chloroform mixture (7/93) to neutralize the TFAand concentrated again to a residue. The residue was purified by flashsilica gel chromatography utilizing a 4 g Thomson normal-phase silicagel cartridge (100% CHCl₃→3:97 MeOH[7N NH₃]:CHCl₃) to afford5-((dimethylamino)methyl)pyridin-3-amine (LVII) (0.044 g, 0.29 mmol, 52%yield) as a brown oil. ESIMS found for C₈H₁₃N₃ m/z 152 (M+H).

The following intermediate was prepared in accordance with the proceduredescribed in the above Scheme 13.

5-((4-Methylpiperazin-1-yl)methyl)pyridin-3-amine (LVIII): Dark yellowsolid (138 mg, 0.67 mmol, 71% yield). ESIMS found for C₁₁H₁₈N₄ m/z 207(M+H).

Preparation of intermediate 6-(pyrrolidin-1-ylmethyl)pyridin-3-amine(LXIII) is depicted below in Scheme 14.

Step 1

To a suspension of methyl 5-nitropicolinate (LIX) (1.282 g, 7.03 mmol)in DCM (25 mL) stirred at −78° C. under argon was slowly added DIBAL (1Min toluene) (9.14 mL, 9.14 mmol). The solution was allowed to warm toroom temperature over 3 h. An aqueous solution of potassium sodiumtartrate was added, diluted further with water and DCM. The solution wasstirred at room temperature for another 30 min before the organic layerwas separated. The aqueous layer was extracted 2×DCM, combined with theorganic layer, dried over MgSO4, filtered and evaporated under reducedpressure. The residue was purified by column chromatography to produce5-nitropicolinaldehyde (LX) as a brown oil (0.64 g, 4.2 mmol, 60%yield). ¹H NMR (DMSO-d₆) δ ppm 8.17 (d, J=9 Hz, 1H), 8.81 (dd, J=9 Hz,J=2 Hz, 1H), 9.56 (d, J=2 Hz, 1H), 10.08 (s, 1H).

Step 2

Preparation of 5-nitro-2-(pyrrolidin-1-ylmethyl)pyridine (LXII) wasperformed following the procedure listed in Scheme 5, Step 1. Purple oil(0.41 g, 1.98 mmol, 86% yield). ¹H NMR (DMSO-d₆) δ ppm 9.28 (d, J=3 Hz,1H), 8.56 (dd, J=11 Hz, 3 Hz, 1H), 7.72 (d, J=11 Hz, 1H), 3.85 (s, 2H),2.53-2.50 (m, 4H), 1.75-1.70 (m, 4H).

Step 3

Preparation of intermediate 6-(pyrrolidin-1-ylmethyl)pyridin-3-amine(LXIII) was performed following the procedure listed in Scheme 11, Step2. Dark brown oil (0.35 g, 1.97 mmol, quantitative). ESIMS found forC₁₀H₁₅N₃ m/z 178 (M+H).

The following intermediate was prepared in accordance with the proceduredescribed in the above Scheme 14.

6-((4-Methylpiperazin-1-yl)methyl)pyridin-3-amine (LXIV): Brown oil (120mg, 0.58 mmol, 100% yield). ESIMS found for C₁₁H₁₈N₄ m/z 207 (M+H).

Preparation of intermediate 6-(3-fluorophenoxy)pyridin-3-amine (LXVIII)is depicted below in Scheme 15.

Step 1

A solution of 2-chloro-5-nitropyridine (LXV) (1.98 g, 12.5 mmol) and3-fluorophenol (LXVI) (1.4 g, 12.5 mmol) in pyridine (20 mL) was heatedat 120° C. overnight under argon. The solution was cooled to roomtemperature and concentrated under vacuum. The residue was dissolved inEtOAc, washed with water, brine, dried over MgSO₄ and evaporated. Theresidue was purified by silica gel column chromatography (100%hexane→2:98 EtOAc:hexane) to give 2-(3-fluorophenoxy)-5-nitropyridine(LXVII) as a yellow viscous oil (2.27 g, 9.7 mmol, 77% yield). ¹H NMR(DMSO-d₆) δ ppm 7.11 (dd, J=8 Hz, J=2 Hz, 1H), 7.17 (dt, J=8 Hz, J=6 Hz,1H), 7.23 (td, J=10 Hz, J=2 Hz, 1H), 7.31 (d, J=9 Hz, 1H), 7.52 (q, J=9Hz, 1H), 8.64 (dd, J=9 Hz, J=3 Hz, 1H), 9.05 (d, J=3 Hz, 1H); ESIMSfound for C₁₁H₇FN₂O₃ m/z 234.9 (M+H).

Step 2

Preparation of intermediate 6-(3-fluorophenoxy)pyridin-3-amine (LXVIII)was performed following the procedure listed in Scheme 11, Step 2. Blackgreen viscous oil (1.90 g, 9.3 mmol, 96% yield). ¹H NMR (DMSO-d₆) δ ppm5.18 (brs, 2H), 6.74-6.83 (m, 3H), 6.90 (dt, 1H), 7.09 (dd, J=9 Hz, J=3Hz, 1H), 7.34 (q, J=7 Hz, 1H), 7.57 (d, J=3 Hz, 1H); ESIMS found forC₁₁H₉FN₂O m/z 204.4 (M+).

The following intermediates were prepared in accordance with theprocedure described in the above Scheme 15.

6-(4-Fluorophenoxy)pyridin-3-amine (LXIX): Dark brown oil (870 mg, 4.3mmol, 100% yield). ¹H NMR (DMSO-d₆) δ ppm 5.08 (brs, 2H), 6.75 (d, J=15Hz, 1H), 6.90-7.01 (m, 2H), 7.07 (dd, J=9 Hz, J=3 Hz, 1H), 7.16 (t, 9Hz, 1H), 7.26-7.30 (m, 1H), 7.73 (d, J=3 Hz, 1H); ESIMS found forC₁₁H₉FN₂O m/z 204.9 (M+H).

6-(2-Fluorophenoxy)pyridin-3-amine (LXX): Dark brown oil (611 mg, 3.0mmol, 91% yield). ESIMS found for C₁₁H₉FN₂O m/z 204.9 (M+H).

Preparation of intermediate 6-phenylpyridin-3-amine (LXXIV) is depictedbelow in Scheme 16.

Step 1

To a solution of 2-bromo-5-nitropyridine (LXXI) (302 mg, 1.49 mmol) in amixture of dioxane (14 mL) and water (3 mL) was added phenylboronic acid(LXXII) (199 mg, 1.64 mmol), Pd(PPh₃)₄ (86 mg, 0.74 mmol) and K₃PO₄ (473mg, 2.23 mmol). The reaction was microwaved at 95° C. for 1 h. Thereaction was cooled and the organic phase was separated, dried overMgSO₄ and evaporated under vacuum. The residue was purified by silicagel column chromatography (100% hexane→5:95 EtOAc:hexane) to give5-nitro-2-phenylpyridine (LXXIII) as off-white needles (254 mg, 1.27mmol, 85% yield). ESIMS found for C₁₁H₈N₂O₂ m/z 200.9 (M+H).

Step 2

Preparation of intermediate 6-phenylpyridin-3-amine (LXXIV) wasperformed following the procedure listed in Scheme 11, Step 2. Blackgreen viscous oil (211 mg, 1.24 mmol, 98% yield). ¹H NMR (DMSO-d₆) δ ppm5.45 (s, 2H), 6.99 (dd, J=11 Hz, J=3 Hz, 1H), 7.25-7.28 (m, 1H),7.38-7.40 (m, 2H), 7.62 (d, J=11 Hz, 1H0, 7.89-7.91 (m, 1H), 8.02 (d,J=3 Hz, 1H); ESIMS found for C₁₁H₁₀N₂ m/z 171 (M+H).

The following intermediates were prepared in accordance with theprocedure described in the above Scheme 16.

6-(3-Fluorophenyl)pyridin-3-amine (LXXV): Brown oil (252 mg, 1.34 mmol,98% yield). ESIMS found for C₁₁H₉FN₂ m/z 189 (M+H).

6-(4-Fluorophenyl)pyridin-3-amine (LXXVI): Deep purple oil (202 mg, 1.07mmol, 98% yield). ESIMS found for C₁₁H₉FN₂ m/z 189 (M+H).

Preparation of intermediate 5-benzylpyridin-3-amine (LXXX) is depictedbelow in Scheme 17.

Step 1

To a solution of 3-bromo-5-nitropyridine (LXXVII) (295 mg, 1.45 mmol) indioxane (14 mL) was added2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (LXXVIII) (420 μL, 1.89mmol), PdCl₂(dppf)₂, (120 mg, 0.15 mmol) and 2M aqueous K₃PO₄ (2.2 mL,4.36 mmol). The reaction was microwaved at 90° C. for 2 h. The reactionwas cooled and the organic phase was separated, dried over MgSO₄ andevaporated under vacuum. The residue was purified by silica gel columnchromatography (100% hexane→6:94 EtOAc:hexane) to give3-benzyl-5-nitropyridine (LXXIX) as brown oil (117 mg, 0.54 mmol, 37%yield). ¹H NMR (DMSO-d₆) δ ppm 4.16 (s, 2H), 7.21-7.25 (m, 1H),7.31-7.33 (m, 4H), 8.45-8.46 (m, 1H), 8.93 (d, J=2 Hz, 1H), 9.21 (d, J=3Hz, 1H); ESIMS found for C₁₂H₁₀N₂O₂ m/z 215 (M+H).

Step 2

Preparation of 5-benzylpyridin-3-amine (LXXX) was performed followingthe procedure listed in Scheme 11, Step 2. Black green viscous oil (139mg, 0.75 mmol, 98% yield). ESIMS found for C₁₂H₁₂N₂ m/z 185 (M+H).

Preparation of intermediate 2-(4-methylpiperazin-1-yl)pyridin-3-amine(LXXXIV) is depicted below in Scheme 18.

Step 1

To a microwave vial was added 2-chloro-3-nitropyridine (LXXXI) (1.00 g,6.31 mmol), 1-methylpiperazine (LXXXII) (0.758 g, 7.57 mmol), cesiumcarbonate (2.88 g, 8.83 mmol), Pd₂(dba)₃ (0.173 g, 0.189 mmol),xanthphos (0.109 g, 0.189 mmol), and dioxane (5 mL). The reaction vialwas capped and purged with argon. The solution into the reaction vialwas heated under microwave irradiation for 2 h at 90° C. The solutionwas filtered through a pad of Celite and concentrated to a residue undervacuum. The residue was purified by column chromatography (1:99MeOH:CHCl₃→8:92 MeOH:CHCl₃) to afford1-methyl-4-(3-nitro-pyridin-2-yl)-piperazine (LXXXIII) (1.30 g, 5.85mmol, 93% yield) as a brown oil.

Step 2

To a stirring solution of 1-methyl-4-(3-nitro-pyridin-2-yl)-piperazine(LXXXIII) (1.30 g, 5.85 mmol) in MeOH (15 mL) was added 10% Pd/C. Thesolution was purged with hydrogen. The solution was stirred at roomtemperature for 16 h under hydrogen. The solution was filtered through apad of Celite and concentrated to a residue under vacuum. The residuewas purified by column chromatography (100% CHCl₃→2:98 MeOH[7NNH₃]:CHCl₃) to afford 2-(4-methylpiperazin-1-yl)pyridin-3-amine (LXXXIV)(0.466 g, 2.42 mmol, 52% yield) as a tan solid. ESIMS found for C₁₀H₁₆N₄m/z 192.4 (M+H).

The following intermediates were prepared in accordance with theprocedure described in the above Scheme 18.

6-(Pyrrolidin-1-yl)pyridin-3-amine (LXXXV): Deep purple oil (1.43 g,8.77 mmol, 100% yield). ESIMS found for C₉H₁₃N₃ m/z 164 (M+H).

6-(4-Methylpiperazin-1-yl)pyridin-3-amine (LXXXVI): Purple solid (598mg, 3.11 mmol, 32% yield). ESIMS found for C₁₀H₁₆N₄ m/z 193 (M+H).

6-Morpholinopyridin-3-amine (LXXXVII): Purple solid (782 mg, 4.36 mmol,95% yield). ESIMS found for C₉H₁₃N₃O m/z 180 (M+H).

N²-(2-(Dimethylamino)ethyl)-N²-methylpyridine-2,5-diamine (LXXXVIII):Deep purple oil (1.55 g, 7.98 mmol, 96% yield). ESIMS found for C₁₀H₁₈N₄m/z 195 (M+H).

Preparation of intermediate 1-(5-aminopyridin-2-yl)piperidin-4-ol (XCI)is depicted below in Scheme 19.

Step 1

To a solution of 2-chloro-5-nitropyridine (LXV) (5.0 g, 31.5 mmol) inDMF (50 mL) was added piperidin-4-ol (LXXXIX) (3.5 g, 34.65 mmol) andK₂CO₃ (8.7 g, 63.0 mmol). The reaction was headed at 85° C. overnight.The solution was poured into ice water, stirred for 15 min and thenfiltered. The solid was washed with cold water and dried under vacuum toproduce 1-(5-aminopyridin-2-yl)piperidin-4-ol (XC) as a yellow solid(6.62 g, 29.67 mmol, 94.2% yield). ¹H NMR (DMSO-d₆) δ ppm 1.34-1.42 (m,2H), 1.77-1.83 (m, 2H), 3.40-3.56 (m, 2H), 3.76-3.83 (m, 1H), 4.12 (brd,2H), 4.81 (d, J=4 Hz, 1H), 6.94 (d, J=10 Hz, 1H), 8.17 (dd, J=10 Hz, J=3Hz, 1H), 8.94 (d, J=3 Hz, 1H); ESIMS found for C₁₀H₁₃N₃O₃ m/z 224.1(M+H).

Step 2

Preparation of intermediate 1-(5-aminopyridin-2-yl)piperidin-4-ol (XCI)was performed following the procedure listed in Scheme 11, Step 2. Darkbrown oil (5.7 g, 29.5 mmol, 99.5% yield). ¹H NMR (DMSO-d₆) δ ppm 1.36(tq, J=13 Hz, J=4 Hz, 2H), 1.72-1.76 (m, 2H), 2.79 (dt, J=13 Hz, J=3 Hz,2H), 3.54-3.61 (m, 1H), 3.70-3.78 (m, 2H), 4.49 (s, 2H), 4.61 (d, J=4Hz, 1H), 6.61 (d, J=9 Hz, 1H), 6.88 (dd, J=9 Hz, J=3 Hz, 1H), 7.57 (d,J=3 Hz, 1H); ESIMS found for C₁₀H₁₅N₃O m/z 194.1 (M+H).

The following intermediates were prepared in accordance with theprocedure described in the above Scheme 19.

6-(Piperidin-1-yl)pyridin-3-amine (XCII): Dark red viscous oil (4.93 g,27.81 mmol, 95.9% yield). ¹H NMR (DMSO-d₆) δ ppm 1.48-1.71 (m, 8H),3.42-3.53 (m, 2H), 4.48 (brs, 2H), 6.59 (d, J=9 Hz, 1H), 6.89 (dd, J=9Hz, J=3 Hz, 1H), 7.58 (d, J=3 Hz, 1H); ESIMS found for C₁₀H₁₅N₃ m/z178.0 (M+H).

5-Methyl-6-(pyrrolidin-1-yl)pyridin-3-amine (XCIII): Dark blue viscousoil (2.06 g, 12.62 mmol, 100% yield). ¹H NMR (DMSO-d₆) δ ppm 1.76-1.82(m, 4H), 2.13 (s, 3H), 3.15-3.20 (m, 4H), 4.53 (brs, 2H), 6.74 (d, J=3.5Hz, 1H), 7.42 (d, J=2.7 Hz, 1H); ESIMS found for C₁₀H₁₅N₃ m/z 178.1(M+H).

6-(Azetidin-1-yl)-5-methylpyridin-3-amine (XCIV): Dark red solid (2.0 g,11.29 mmol, 86.9% yield). ¹H NMR (DMSO-d₆) δ ppm 2.11 (quin, J=7 Hz,2H), 3.76-3.87 (m, 4H), 4.50 (brs, 2H), 6.72 (d, J=2.5 Hz, 1H), 7.38 (d,J=2.5 Hz, 1H); ESIMS found for C₉H₁₃N₃ m/z 164.4 (M+H).

6-(Azetidin-1-yl)pyridin-3-amine (XCV): Burgundy solid (1.45 g, 9.70mmol, 99.3% yield). ESIMS found for C₈H₁₁N₃ m/z 149.0 (M+H).

Preparation of intermediate tert-butyl4-(5-aminopyridin-2-yl)piperazine-1-carboxylate (XCVIII) is depictedbelow in Scheme 20.

Step 1

To a solution of 2-chloro-5-nitropyridine (LXV) (2.0 g, 12.6 mmol) inEtOH (20 mL) was added A/V-butyl piperazine-1-carboxylate (XCVI) (7.05g, 37.9 mmol). The reaction was headed at 70° C. for 16 h. The reactionwas concentrated under vacuum and then dissolved in EtOAc. The EtOAc waswashed with 1 M NaOH, brine and then dried over MgSO4 to give tert-butyl4-(5-nitropyridin-2-yl)piperazine-1-carboxylate (XCVII) as a yellowsolid (4.94 g). ESIMS found for C₁₄H₂₀N₄O₄ m/z 309.0 (M+H).

Step 2

Preparation of intermediate tert-butyl4-(5-aminopyridin-2-yl)piperazine-1-carboxylate (XCVIII) was performedfollowing the procedure listed in Scheme 11, Step 2. Purple solid (990mg, 3.56 mmol, quantitative). ESIMS found for C₁₄H₂₂N₄O₂ m/z 278.8(M+H).

Preparation of intermediate N-(3-aminopyridin-4-yl)cyclopropanecarboxamide (CII) is depicted below in Scheme 21.

Step 1

Preparation of N-(3-nitropyridin-4-yl)cyclopropanecarboxamide (CI) wasperformed following the procedure listed in Scheme 4, Step 1. Orangesolid (130 mg, 0.93 mmol, 13% yield). ESIMS found for C₉H₉N₃O₃ m/z 207.8(M+H).

Step 2

Preparation of intermediate N-(3-aminopyridin-4-yl)cyclopropanecarboxamide (CII) was performed following the procedurelisted in Scheme 11, Step 2. Dark grey solid (100 mg, 0.56 mmol,quantitative). ESIMS found for C₉H₁₁N₃O m/z 178.3 (M+H).

Preparation of intermediate(5-aminopyridin-2-yl)(pyrrolidin-1-yl)methanone (CV) is depicted belowin Scheme 22.

Step 1

To a solution of 5-nitropicolinic acid (CIII) (500 mg, 2.97 mmol) in DMF(15 mL) was added pyrrolidine (244 μl, 2.47 mmol) and DIPEA (1.03 mL,5.95 mmol). The reaction was cooled at 0° C. before adding HATU (1.13 g,2.47 mmol). The reaction was warmed to room temperature and stirred for2 hrs. The reaction was concentrated under vacuum and then dissolved ina mixture of water and 10% iPrOH/CHCl₃. The organic layer was separatedand the aqueous phase was washed again with 10% iPrOH/CHCl₃. Thecombined organic phases were washed with brine, dried over MgSO4 andevaporated to yield (5-nitropyridin-2-yl)(pyrrolidin-1-yl)methanone(CIV) as a red solid (849 mg). ESIMS found for C₁₀H₁₁N₃O₃ m/z 222.1(M+H).

Step 2

Preparation of intermediate(5-aminopyridin-2-yl)(pyrrolidin-1-yl)methanone (CV) was performedfollowing the procedure listed in Scheme 11, Step 2. Yellow solid (708mg, 7.3 mmol, 96.4% yield). ESIMS found for C₁₀H₁₃N₃O m/z 191.4 (M+H).

The following intermediate was prepared in accordance with the proceduredescribed in the above Scheme 22.

5-Amino-N-cyclopentylpicolinamide (CVI): Yellow solid (450 mg, 2.19mmol, 93.7% yield). ESIMS found for C₁₁H₁₅N₃O m/z 206.1 (M+H).

Preparation of intermediate 6-(methylsulfonyl)pyridin-3-amine (CIX) isdepicted below in Scheme 23.

Step 1

To a solution of sodium thiomethoxide in THF (53 mL) and H₂O (20 mL)cooled to 0° C. was added 2-chloro-5-nitropyridine (LXV) (5.09 g, 32.09mmol). The reaction was warmed to room temperature and stirred for 2hrs. The reaction was poured into ice water and stirred for 10 minutes,filtered, washed with water, dried under vacuum to yield2-(methylthio)-5-nitropyridine (CVII) as a yellow solid (5.14 g, 30.20mmol, 94.1%). ¹H NMR (DMSO-d₆) δ ppm 2.62 (s, 3H), 7.57 (d, J=8.9 Hz,1H), 8.38 (d, J=8.9 Hz, 1H), 9.22 (d, J=2.7 Hz, 1H); ESIMS found forC₆H₆N₂O₂S m/z 171.1 (M+H).

Step 2

To a solution of 2-(methylthio)-5-nitropyridine (CVII) (502 mg, 2.95mmol) in DCM (60 mL) was mCPBA (1.33 g, 5.90 mmol). The reaction wasstirred at room temperature for 1 hr. Two additional portions of mCPBA(2×250 mg) were added at 1 hr intervals for a total reaction time of 4hr. The reaction was poured into saturated aqueous NaHCO₃. The organicphase was separated and washed with water, brine and then dried overMgSO4. The solvent was removed under vacuum to produce crude2-(methylsulfonyl)-5-nitropyridine (CVIII) (854 mg) which was usedwithout purification for step 3. ESIMS found for C₆H₆N₂O₄S m/z 203.0(M+H).

Step 3

Preparation of intermediate 6-(methylsulfonyl)pyridin-3-amine (CIX) wasperformed following the procedure listed in Scheme 11, Step 2. The crudeproduct was used as is without purification. ESIMS found for C₆H₈N₂O₂Sm/z 173.0 (M+H).

Preparation of intermediate5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (CXIV) isdepicted below in Scheme 24.

Step 1

1H-indazole-3-carboxylic acid (CX) (100 g, 617 mmol) in DMF was treatedwith carbonyldiimidazole (110 g, 678 mmol) at room temperature until theevolution of gas ceased (ca. 15 minutes). The reaction was heated to60-65° C. for 2 h and then allowed to cool to room temperature.N,O-Dimethylhydroxylamine-HCl (66.2 g, 678 mmol) was added as a solidand the mixture was heated to 65° C. for 3 h. The reaction wasconcentrated to a paste, taken up in DCM and washed subsequently withwater and 2 N HCl. The product could be seen coming out of solution. Thesolid was filtered and rinsed separately with EtOAc. The EtOAc and DCMlayers were separately washed with sodium bicarbonate followed by brine,dried over MgSO₄ and concentrated under reduced pressure. The resultingsolids were combined, triturated with 1:1 mixture of DCM-ether,filtered, and dried to produceN-methoxy-N-methyl-1H-indazole-3-carboxamide (CXI) as a white solid (100g, 487 mmol, 79% yield). ¹H NMR (DMSO-d₆) δ ppm 3.46 (s, 3H), 3.69-3.85(m, 3H), 7.13-7.31 (m, 1H), 7.41 (t, J=7.25 Hz, 1H), 7.56-7.65 (m, 1H),7.93-8.08 (m, 1H); ESIMS found for C₁₀H₁₁N₃O₂ m/z 206 (M+H).

Step 2

To N-methoxy-N-methyl-1H-indazole-3-carboxamide (CXI) (20 g, 97.4 mmol)in DCM (1 L) was added (Bis(trifluoroacetoxy)iodo)benzene (46 g, 107mmol) followed by portionwise addition of iodine (14.84 g, 58.5 mmol) atroom temperature. After 1 h, saturated aqueous NaHSO₃ (600 mL) was addedand a solid began to precipitate which was filtered and rinsed withexcess DCM. The filtrate was washed with brine, dried over MgSO₄,concentrated and the remaining solid was triturated with a minimalamount of DCM. The combined solids were dried under vacuum over KOH toproduce 5-iodo-N-methoxy-N-methyl-1H-indazole-3-carboxamide (CXII) as awhite solid (23.2 g, 70 mmol, 72% yield). ¹H NMR (DMSO-d₆) δ ppm 3.45(s, 3H), 3.77 (s, 3H), 7.45-7.54 (m, 1H), 7.66 (dd, J=8.81, 1.51 Hz,1H), 8.40 (d, J=1.01 Hz, 1H); ESIMS found for C₁₀H₁₀N₃O₂ m/z 331 (M+H).

Step 3

A mixture of 5-iodo-N-methoxy-N-methyl-1H-indazole-3-carboxamide (CXII)(16.5 g, 50 mmol), 3,4-dihydro-2H-pyran (10.3 mL, 113 mmol) and PPTS(0.12 g, 0.6 mmol) in DCM was heated to reflux for 5 h. The solution waspoured into a saturated aqueous NaHCO₃ solution, the layers wereseparated, and the aqueous layer was extracted with DCM. The combinedorganic layers were washed with 5% aqueous citric acid and brine, driedover MgSO₄, and concentrated. The crude product was purified on a silicagel column (100% EtOAc→3:97 MeOH:DCM) to provide5-iodo-N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide(CXIII) as a white viscous oil (19.1 g, 46 mmol, 92% yield). ¹H NMR(DMSO-d₆) δ ppm 1.28-1.84 (m, 6H), 3.43 (s, 3H), 3.60-4.04 (s, 5H),5.86-6.08 (m, 1H), 7.45-7.87 (m, 2H), 8.39 (s, 1H); ESIMS found forC₁₅H₁₈N₃O₃ m/z 416 (M+H).

Step 4

Lithium aluminum hydride (160 mg, 4.21 mmol) was added in portions to acooled (0° C.) solution of5-iodo-N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide(CXIII) (1.46 g, 3.5 mmol) in THF. Stirring was continued at 0° C. untilthe reaction was completed, approximately 30 min. The reaction wasquenched by the slow addition of EtOAc at 0° C., and the whole mixturewas poured into 0.4 N aqueous NaHSO₄. The organic layer was washed withbrine, dried over MgSO₄, concentrated, and purified on a silica gelcolumn (100% EtOAc→3:97 MeOH:DCM) to give5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (CXIV) asa white solid (0.90 g, 3.15 mmol, 72% yield). ¹H NMR (DMSO-d₆) δ ppm1.50-1.71 (m, 2H), 1.71-1.87 (m, 1H), 1.97-2.15 (m, 2H), 2.31-2.42 (m,1H), 3.66-3.99 (m, 2H), 5.96-6.17 (m, 1H), 7.78 (d, J=6 Hz, 1H), 7.84(d, J=6 Hz, 1H), 8.50 (s, 1H), 10.13 (s, 1H); ESIMS found forC₁₃H₁₃IN₂O₂ m/z 357 (M+H).

Preparation of intermediate5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid(CXVIII) is depicted below in Scheme 25.

Step 1

A suspension of indazole-3-carboxylic acid (CX) (1.0 g, 6.16 mmol) inglacial acetic acid (60 mL) was heated at 120° C. to get a clearsolution. The solution was cooled to 90° C. A solution of bromine (0.633mL, 12.33 mmol) in glacial acetic acid (2 mL) was added slowly to thesolution while heating at 90° C. The solution was further heated 16 h at90° C. The solution was cooled to room temperature, poured into icewater and further stirred at room temperature for 15 min. The solidsformed were filtered, washed with cold water and dried under vacuum atroom temperature to get 5-bromo-1H-indazole-3-carboxylic acid (CXV) as awhite solid (1.30 g, 5.39 mmol, 87.5% yield). ¹H NMR (DMSO-d₆) δ ppm13.95 (s, 1H), 13.18 (br s, 1H), 8.21 (d, J=1.2 Hz, 1H), 7.65 (d, J=7.0Hz, 1H), 7.56 (dd, J=7.0, 1.2 Hz, 1H); ESIMS found for C₈H₄BrN₂O₂ m/z242.0 (M+H).

Step 2

Concentrated sulfuric acid (1 mL) was added to a suspension of5-bromo-1H-indazole-3-carboxylic acid (CXV) (1.30 g, 5.39 mmol) in dryMeOH (50 mL) and heated to reflux for 4 h under argon. The solution wascooled to room temperature and the MeOH was evaporated under vacuum. Theresidue was dissolved in EtOAc and washed with water. The organic phasewas dried over Na₂SO₄, filtered and concentrated to afford methyl5-bromo-1H-indazole-3-carboxylate (CXVI) as a white solid (1.35 g, 5.29mmol, 98% yield). ¹H NMR (DMSO-d₆) δ ppm 14.13 (s, 1H), 8.21 (d, J=1.6Hz, 1H), 7.67 (d, J=12 Hz, 1H), 7.59 (dd, J=72, 1.2 Hz, 1H), 3.92 (s,3H); ESIMS found for C₉H₇BrN₂O₂ m/z 256.0 (M+H).

Step 3

A suspension of methyl 5-bromo-1H-indazole-3-carboxylate (CXVI) (1.35 g,5.29 mmol), pyridinium p-toluenesulfonate (0.143 g, 0.56 mmol) and 3,4dihydro-2H-pyran (1.02 mL, 11.90 mmol) in anhydrous dichloroethane (20mL) was refluxed 5 h under argon. The suspension was turned into theclear solution. The solution was cooled and the excess solvent wasevaporated under vacuum. The residue was dissolved in EtOAc and washedwith dilute NaHCO₃ solution (sat^(d). NaHCO₃ sol MHO: 1:9). The organiclayer was dried over Na₂SO₄, filtered and concentrated. The residue waspurified by column chromatography (100% hexanes→5:95 EtOAc:hexanes) toget methyl5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylate (CXVII)as a white solid (1.47 g, 4.34 mmol, 82% yield). ¹H NMR (DMSO-d₆) δ ppm8.22 (d, J=1.4 Hz, 1H), 7.89 (d, J=7.2 Hz, 1H), 7.68 (dd, J=7.2, 1.6 Hz,1H),), 6.02 (dd, J=8.0, 2.4 Hz, 1H), 3.94 (s, 3H), 3.88 (m, 1H), 3.79(m, 1H), 2.37-2.31 (m, 1H), 2.05-1.96 (m, 2H), 1.77-1.73 (m, 1H).1.60-1.58 (m, 2H); ESIMS found for C₁₄H₁₅BrN₂O₃ m/z 340.0 (M+H).

Step 4

2 N Aqueous NaOH solution (10 mL) was added to a suspension of methyl5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylate (CXVII)(1.30 g, 3.83 mmol) in water (20 mL) and heated at 90° C. for 1 h. Thesolution was cooled to room temperature, diluted with ice water andacidified to pH 3.0 with 10% aqueous HCl. The solids formed werefiltered, washed with cold water and dried under vacuum at roomtemperature to get5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid(CXVIII) as a white solid (0.87 g, 2.68 mmol, 70% yield). ESIMS foundfor C₁₃H₁₃BrN₂O₃ m/z 326.0 (M+H).

Step 5

To a solution of 5-bromo-1H-indazole-3-carboxylic acid (CXV) (59.8 g,248 mmol) in THF (800 mL) under argon was added 3,4 dihydro-2H-pyran(50.6 mL, 558 mmol) and p-TsOH (4.72 g, 24.8 mmol). The reaction washeated to reflux at 60° C. for 16 h. An additional portion of p-TsOH(0.025 eq) and 3,4 dihydro-2H-pyran (0.56 eq) was added and the refluxcontinued for 5 h. The solution was concentrated under vacuum. EtOAc wasadded to the residue and the suspension was filtered and dried underhigh vacuum overnight to produce5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid(CXVIII) as a white solid (49.07 g, 150.9 mmol, 60.8% yield). ESIMSfound for C₁₃H₁₃BrN₂O₃ m/z 326.3 (M+H).

Preparation of intermediate 5-bromo-1-trityl-1H-indazole-3-carboxylicacid (CXXI) is depicted below in Scheme 26.

Step 1

Preparation of intermediate ethyl 5-bromo-1H-indazole-3-carboxylate(CXIX) was performed following the procedure listed in Scheme 25, Step2. White solid. (3.60 g, 13.38 mmol, 64.5% yield). ¹H NMR (DMSO-d₆) δppm 1.37 (t, J=7 Hz, 3H), 4.40 (q, J=7 Hz, 2H), 7.57 (dd, J=9 Hz, J=2Hz, 1H), 7.66 (d, J=9 Hz, 1H), 8.20 (d, J=2 Hz, 1H), 14.11 (brs, 1H);ESIMS found for C₁₀H₉BrN₂O₂ m/z 269.0 (M+H).

Step 2

To a solution of ethyl 5-bromo-1H-indazole-3-carboxylate (CXIX) andtrityl chloride in DCM was slowly added DIPEA. The solution was stirredat room temperature overnight. The reaction was poured into water andstirred for 5 min. The organic layer was separated, dried over MgSO₄ andconcentrated under vacuum. The residue was purified by columnchromatography using a ISCO 200RF system with a SiO₂ column (12 g) (100%hexanes→10:90 EtOAc:hexanes) to produce a white solid. (357 mg, 0.70mmol, 69.8% yield). ¹H NMR (DMSO-d₆) δ ppm 1.34 (t, J=7 Hz, 3H), 4.38(q, J=7 Hz, 2H), 6.43 (d, J=9.5 Hz, 1H), 7.11-7.14 (m, 6H), 7.31-7.35(m, 10H), 8.23 (d, J=2 Hz, 1H); ESIMS found for C₂₉H₂₃BrN₂O₂ m/z 511.0(M+H).

Step 3

Preparation of intermediate 5-bromo-1-trityl-1H-indazole-3-carboxylicacid (CXXI) by hydrolysis of ethyl5-bromo-1-trityl-1H-indazole-3-carboxylate (CXX) can be performedfollowing the procedure listed in Scheme 25, Step 3.

Step 4

Preparation of intermediate 5-bromo-1-trityl-1H-indazole-3-carboxylicacid (CXXI) by tritylation of 5-bromo-1H-indazole-3-carboxylic acid(CXV) can be performed following the procedure listed in the Journal ofMedicinal Chemistry (2003), 46(25), 5458-5470.

Example 1

Preparation of5-(5-(3,3-dimethylureido)pyridin-3-yl)-N-(pyridin-3-yl)-1H-indazole-3-carboxamide(1) is depicted below in Scheme 27.

Step 1-2

A solution of5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (CXIV)(1.780 g, 5.0 mmol), bis(pinacolato)diboron (1.523 g, 6.0 mmol), KOAc(1.471 g, 15 mmol) and dry DMF (20 mL) was purged with argon.PdCl₂(dppf)₂ (0.245 g, 0.3 mmol) was added to the reaction and purgedagain with argon. The solution was heated at 90° C. for 2 h. Once TLCshowed the disappearance of (CXIV), the solution was cooled to roomtemperature. To this solution was added K₃PO₄ (1.592 g, 7.5 mmol),3-(5-bromopyridin-3-yl)-1,1-dimethylurea (XXII) (1.220 g, 5.0 mmol),Pd(PPh₃)₄ (173 mg, 0.15 mmol) and water (2 mL). The solution was purgedwith argon and heated at 90° C. for 3 h. The solution was cooled to roomtemperature and then concentrated under reduced pressure. The residuewas dissolved in DCM and washed with water, dried over MgSO₄, filteredand then evaporated under vacuum. The residue was purified on a silicagel column (100% DCM→2:98 MeOH:DCM) to give3-(5-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-1,1-dimethylurea(CXXIII) as a brown viscous oil which solidified under vacuum at roomtemperature (354 mg, 0.90 mmol, 18% yield for 2 steps). ¹H NMR (DMSO-d₆)δ ppm 10.22 (s, 1H), 8.76 (d, J=1.6 Hz, 1H), 8.63 (s, 1H), 8.52 (d,J=1.6 Hz, 1H), 8.36 (s, 1H), 8.24 (m, 1H), 8.05 (d, J=7.2 Hz, 1H), 7.91(dd, J=7.2, 1.4 Hz, 1H), 6.13 (dd, J=7.6, 2.0 Hz, 1H), 3.93 (m, 1H),3.85 (m, 1H), 2.98 (s, 6H), 2.47-2.42 (m, 1H), 2.11-2.06 (m, 2H),1.82-1.79 (m, 1H) 1.64 (m, 2H); ESIMS found for C₂₁H₂₃N₅O₃ m/z 394.0(M+H).

Step 3

A solution of sodium hydroxide (0.173 g, 4.33 mmol) in water (5 mL) wasadded to a solution of silver nitrate (0.367 g, 2.16 mmol) in water (5mL) to give a brown precipitate.3-(5-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-1,1-dimethylurea (CXXIII) (0.340 g, 0.86 mmol) wasdissolved in 1,4-dioxane (10 mL) and added to the reaction which wasstirred overnight at room temperature. The solution was diluted withwater and then extracted with diethyl ether. The aqueous layer wasseparated and carefully brought to pH=3 with aqueous HCl. The aqueouslayer was then extracted with 10% iPrOH/chloroform. The combined organiclayers were then dried (Na₂SO₄), filtered and concentrated to give5-(5-(3,3-dimethylureido)pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylicacid (CXXIV) as a brownish white solid (246 mg, 0.60 mmol, 70% yield).¹H NMR (DMSO-d₆) δ ppm 13.26 (br. s, 1H), 8.87 (s, 1H), 8.63 (s, 1H),8.41 (s, 1H), 8.34 (s, 1H), 8.03 (d, J=7.1 Hz, 1H), 7.86 (dd, J=7.2, 1.3Hz, 1H), 6.06 (dd, J=8.0, 4.0 Hz, 1H), 3.92 (m, 1H), 3.80 (m, 1H), 2.98(s, 6H), 2.42-2.39 (m, 1H), 2.03-2.02 (m, 2H), 1.79-1.77 (m, 1H) 1.61(m, 2H); ESIMS found for C₂₁H₂₃N₅O₄ m/z 410.0 (M+H).

Step 4

HATU (0.190 g, 0.5 mmol) was added to a solution of5-(5-(3,3-dimethylureido)pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylicacid (CXXIV) (0.39 g, 1.21 mmol) and diisopropylethylamine (0.174 mL,1.0 mmol) in DMF stirred at room temperature under argon. After stirring5 min, the solution was added with 3-aminopyridine (CXXV) (0.047 g, 0.5mmol). The solution was stirred overnight at room temperature underargon. The DMF was removed under reduced pressure, and the residue wastreated with water, sonicated briefly and filtered. The solids werewashed with cold water and dried at room temperature. The product waspurified by column chromatography using a 4 g Thomson normal phasesilica gel cartridge (100% DCM→5:95 MeOH:DCM) to afford5-(5-(3,3-dimethylureido)pyridin-3-yl)-N-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide(CXXVI) as an off white solid (323 mg, 0.67 mmol, 55% yield). ¹H NMR(DMSO-d₆) δ ppm 10.56 (s, 1H), 9.06 (d, 7=2.0 Hz, 1H), 8.75 (d, J=1.6Hz, 1H), 8.64 (s, 1H), 8.53 (d, J=1.6 Hz, 1H), 8.46 (s, 1H), 8.34-8.29(m, 2H), 8.26 (m, 1H), 8.03 (d, J=7.0 Hz, 1H), 7.88 (dd, J=7.0, 1.2 Hz,1H), 7.43 (dd, J=6.64, 3.84 Hz, 1H), 6.07 (dd, J=8.0, 1.8 Hz, 1H), 3.98(m, 1H), 3.82 (m, 1H), 2.98 (s, 6H), 2.63-2.60 (m, 1H), 2.11-2.06 (m,2H), 1.83-1.81 (m, 1H) 1.52 (m, 2H); ESIMS found for C₂₁H₂₃N₅O₄ m/z410.0 (M+H).

Step 5

TFA (5 mL) was added to a solution of5-(5-(3,3-dimethylureido)pyridin-3-yl)-N-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide(CXXVI) (0.134 g, 0.27 mmol) and triethylsilane (0.110 mL, 0.69 mmol) inDCM (5 mL) and stirred 3 h at room temperature. The solvent was removedunder vacuum. The residue was treated with water, sonicated briefly todisperse the solids, basified to pH 9.0 with 5 N NH₄OH and sonicatedagain. The solids were filtered, washed with cold water and purified bycolumn chromatography (100% DCM→5:95 MeOH[7N NH₃]:DCM) to afford5-(5-(3,3-dimethylureido)pyridin-3-yl)-N-(pyridin-3-yl)-1H-indazole-3-carboxamide(1) as a white solid (35.8 mg, 0.09 mmol, 33% yield). ¹H NMR (DMSO-d₆) δppm 13.99 (s, 1H), 10.69 (s, 1H), 9.08 (d, J=1.2 Hz, 1H), 8.74 (d, J=1.8Hz, 1H), 8.63 (s, 1H), 8.51 (d, J=1.5 Hz, 1H), 8.47 (s, 1H), 8.33-8.30(m, 2H), 8.26 (m, 1H), 7.80 (s, 2H), 7.41 (dd, J=6.6, 3.6 Hz, 1H), 2.98(s, 6H); ESIMS found for C₂₁H₁₉N₇O₂ m/z 402.3 (M+H).

The following compound was prepared in accordance with the proceduredescribed in the above Example 1.

N-(5-Fluoropyridin-3-yl)-5-(pyridin-3-yl)-1H-indazole-3-carboxamide 23

Light tan solid. ¹H NMR (DMSO-d₆) δ ppm 7.53 (dd, J=8 Hz, J=5 Hz, 1H),7.82-7.86 (m, 2H), 8.13-8.15 (m, 1H), 8.31-8.34 (m, 2H), 8.47-8.48 (m,1H), 8.60 (dd, J=5 Hz, J=2 Hz, 1H), 894 (d, J=2 Hz, 1H), 8.99 (d, J=2Hz, 1H), 10.97 (s, 1H), 14.05 (s, 1H); ESIMS found for C₁₈H₁₂FN₃O m/z334 (M+1).

Example 2

Preparation of5-(5-fluoropyridin-3-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-1H-indazole-3-carboxamide(2) is depicted below in Scheme 28.

Step 1

HATU (1.125 g, 2.96 mmol) was added to a solution of5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid(CXVIII) (0.876 g, 2.69 mmol) and diisopropylethylamine (1.03 mL, 5.92mmol) in DMF stirred at room temperature under argon. After stirring 5min, the solution was added with 5-amino-2-trifluoromethyl pyridine(CXXVII) (0.479 g, 2.96 mmol). The solution was stirred 24 h at roomtemperature under argon. The DMF was removed under reduced pressure, andthe residue was treated with water, sonicated briefly and filtered. Thesolids were washed with cold water and dried at room temperature. Theproduct was purified by silica gel column chromatography (100%hexanes→7:93 EtOAc:hexanes) to afford5-bromo-1-(tetrahydro-2H-pyran-2-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-1H-indazole-3-carboxamide(CXXVIII) as a white solid (1.17 g, 2.50 mmol, 93% yield). ¹H NMR(DMSO-d₆) δ ppm 10.93 (s, 1H), 9.23 (d, J=1.9 Hz, 1H), 8.60 (dd, J=6.8,1.4 Hz, 1H), 8.38 (d, J=4.4 Hz, 1H), 7.95 (m, 2H), 7.70 (dd, J=7.1, 1.5Hz, 1H),), 6.04 (dd, J=8.1, 1.9 Hz, 1H), 3.98 (m, 1H), 3.82 (m, 1H),2.59-2.54 (m, 1H), 2.08-2.03 (m, 2H), 1.81-1.77 (m, 1H). 1.66-1.61 (m,2H); ESIMS found for C₁₉H₁₆BrF₃N₄O₂ m/z 470.0 (M+H).

Step 2

A solution of5-bromo-1-(tetrahydro-2H-pyran-2-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-1H-indazole-3-carboxamide (CXXVIII) (0.469 g, 1 mmol),5-fluoro-pyridyl-3-boronic acid (CXXIX) (0.156 g, 1.1 mmol), potassiumphosphate tribasic (0.318 g, 1.5 mmol) and water (degassed, 1 mL) in DMF(10 mL) was purged with argon. Tetrakis(triphenylphosphine)palladium(O)(0.034 g, 0.03 mmol) was added and the solution was purged again withargon. The reaction was heated to 90° C. for 3 h when TLC showeddisappearance of starting material. The solution was cooled to roomtemperature and excess solvent was removed under vacuum. The residue wastreated with water, sonicated briefly and the solids formed werefiltered. The solids were washed with cold water and dried under vacuumat room temperature which was purified by silica gel columnchromatography (2:8 EtOAc:hexanes→3:7 EtOAc:hexanes) to afford5-(5-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-1H-indazole-3-carboxamide (CXXX) as a white solid (427 mg,0.88 mmol, 88% yield). ¹H NMR (DMSO-d₆) δ ppm 10.95 (s, 1H), 9.25 (d,J=1.8 Hz, 1H), 8.85 (m, 1H), 8.63 (d, J=1.8 Hz, 1H), 8.61 (d, J=2.1 Hz,1H), 8.53 (m, 1H), 8.16-8.13 (m, 1H), 8.08 (d, J=7.1 Hz, 1H), 7.97-7.94(m, 2H), 6.11 (dd, J=8.1, 1.8 Hz, 1H), 4.01 (m, 1H), 3.88-3.83 (m, 1H),2.63-2.60 (m, 1H), 2.11-2.07 (m, 2H), 1.83-1.80 (m, 1H). 1.69-1.65 (m,2H); ESIMS found for m/z 486.0 (M+H).

Step 3

TFA (10 mL) was added to a solution of5-(5-fluoropyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-1H-indazole-3-carboxamide(CXXX) (0.420 g, 0.86 mmol) and triethyl silane (0.345 mL, 2.16 mmol) inDCM (10 mL) and stirred 5 h at room temperature. The solvent was removedunder vacuum. The residue was treated with water, sonicated briefly todisperse the solids, basified to pH 9.0 with 5 N NH₄OH and sonicatedagain. The solids were filtered, washed with cold water and air dried atroom temperature. The solids were suspended in DCM:MeOH (1:1) mixtureand boiled to get a clear solution. The solution was cooled to roomtemperature. The solids formed were filtered washed with DCM and driedunder vacuum at room temperature to get5-(5-fluoropyridin-3-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-1H-indazole-3-carboxamide(2) as a white solid (72.9 mg, 0.18 mmol, 21% yield). ¹H NMR (DMSO-d₆) δppm 14.13 (br. s, 1H), 11.11 (s, 1H), 9.27 (d, J=1.8 Hz, 1H), 8.84 (m,1H), 8.63 (dd, J=6.8, 1.8 Hz, 1H), 8.60 (d, J=2.0 Hz, 1H), 8.53 (m, 1H),8.14-8.11 (m, 1H), 7.94 (d, J=6.9 Hz, 1H), 7.90-7.83 (m, 2H); ESIMSfound for C₁₉H₁₁F₄N₅O m/z 402.30 (M+H).

The following compound was prepared in accordance with the proceduredescribed in the above Example 2.

5-(Pyridin-3-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-1H-indazole-3-carboxamide3

White solid (19% yield). ¹H NMR (DMSO-d₆) δ ppm 14.03 (br. s, 1H), 11.10(s, 1H), 9.27 (d, J=1.8 Hz, 1H), 8.94 (d, J=1.6 Hz, 1H), 8.63 (dd,J=6.8, 1.7 Hz, 1H), 8.60 (m, 1H), 8.48 (s, 1H), 8.15-8.13 (m, 1H), 7.93(d, J=6.9 Hz, 1H), 7.85 (s, 2H), 7.54 (m, 1H); ESIMS found forC₁₉H₁₂F₃N₅O m/z 384.0 (M+H).

N-(1-Methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-(pyridin-3-yl)-1H-indazole-3-carboxamide37

Light green solid (76.7 mg, 0.20 mmol, 48.4% yield). ¹H NMR (DMSO-d₆) δppm 3.93 (s, 3H), 7.18 (s, 1H), 7.55 (dt, J=8 Hz, J=3 Hz, 1H), 7.81 (dd,J=15 Hz, J=9 Hz, 2H), 8.16 (d, J=8 Hz, 1H), 8.45 (s, 1H), 8.61 (d, J=4Hz, 1H), 8.95 (s, 1H), 10.81 (s, 1H), 13.96 (s, 1H); ESIMS found forC₁₈H₁₃F₃N₆O m/z 387.1 (M+H).

5-(Pyridin-3-yl)-N-(pyridin-3-ylmethyl)-1H-indazole-3-carboxamide 42

White solid (54.5 mg, 0.17 mmol, 78% yield). ¹H NMR (DMSO-d₆) δ ppm 4.53(d, J=6 Hz, 2H), 7.35 (dd, J=8 Hz, J=5 Hz, 1H), 7.49-7.52 (m, 1H),7.74-7.78 (m, 3H), 8.09-8.11 (m, 1H), 8.41-8.42 (m, 1H), 8.45 (dd, J=5Hz, J=2 Hz, 1H), 8.57 (dd, J=5 Hz, J=2 Hz, 1H), 8.59 (d, J=2 Hz, 1H),8.90 (d, J=2 Hz, 1H), 9.16 (t, J=6 Hz, 1H), 13.77 (s, 1H); ESIMS foundfor C₁₈H₁₅N₅O m/z 330 (M+H).

5-(Pyridin-3-yl)-N-(4-(trifluoromethyl)pyridin-3-yl)-1H-indazole-3-carboxamide48

White solid (67 mg, 0.17 mmol, 62% yield). ¹H NMR (DMSO-d₆) δ ppm 7.52(dd, J=8 Hz, J=5 Hz, 1H), 7.83-7.87 (m, 3H), 8.12 (td, J=8 Hz, J=2 Hz,1H), 8.41 (t, J=1 Hz, 1H), 8.59 (dd, J=5 Hz, J=2 Hz, 1H), 8.75 (d, J=5Hz, 1H), 8.92 (d, J=3 Hz, 1H), 9.08 (s, 1H), 10.21 (s, 1H), 14.06 (brs,1H); ESIMS found for C₁₉H₁₂F₃N₅O m/z 384.0 (M+H).

5-(Pyridin-3-yl)-N-(6-(pyrrolidin-1-yl)pyridin-3-yl)-1H-indazole-3-carboxamide53

Beige solid (23.8 mg, 0.06 mmol, 44.5% yield). ¹H NMR (DMSO-d₆) δ ppm1.92-1.97 (m, 4H), 3.38 (t, J=7 Hz, 4H), 6.46 (d, J=9 Hz, 1H), 7.52 (dd,J=8 Hz, J=5 Hz, 1H), 7.80 (dq, J=9 Hz, J=2 Hz, 2H), 7.97 (dd, J=9 Hz,J=3 Hz, 1H), 8.12 (dd, J=8 Hz, J=4 Hz, 1H), 8.47 (s, 1H), 8.50 (d, J=3Hz, 1H), 8.59 (dd, J=5 Hz, J=2 Hz, 1H), 8.92 (d, J=2 Hz, 1H), 10.22 (s,1H), 13.86 (s, 1H); ESIMS found for C₂₂H₂₀N₆O m/z 385.1 (M+H).

N-(4-(Cyclopropanecarboxamido)pyridin-3-yl)-5-(pyridin-3-yl)-1H-indazole-3-carboxamide58

White solid (32.7 mg, 0.08 mmol, 37.0% yield). ¹H NMR (DMSO-d₆) δ ppm0.84-0.88 (m, 2H), 0.88-0.92 (m, 2H), 1.91-1.99 (m, 1H), 7.52 (dd, J=8Hz, J=5 Hz, 1H), 7.73 (d, J=6 Hz, 1H), 7.82 (dd, J=12 Hz, J=9 Hz, 2H),8.12 (dt, J=9 Hz, J=4 Hz, 1H), 8.34 (d, J=6 Hz, 1H), 8.44 (s, 1H), 8.59(dd, J=5 Hz, J=2 Hz, 1H), 8.80 (s, 1H), 8.92 (d, J=2 Hz, 1H), 10.03 (s,1H), 10.31 (s, 1H), 13.98 (s, 1H); ESIMS found for C₂₂H₁₈N₆O₂ m/z 399.0(M+H).

N-(6-(Cyclopentylcarbamoyl)pyridin-3-yl)-5-(pyridin-3-yl)-1H-indazole-3-carboxamide181

Light yellow solid (18 mg, 0.04 mmol, 16.6% yield). ¹H NMR (DMSO-d₆) δppm 1.50-1.64 (m, 4H), 1.67-1.76 (m, 2H), 1.85-1.94 (m, 4H), 4.24 (quin,J=8 Hz, 1H), 7.53 (dd, J=8 Hz, J=5 Hz, 1H), 7.84 (ABq, 2H), 8.03 (d, J=9Hz, 1H), 8.14 (d, J=8 Hz, 1H), 8.45 (d, J=8 Hz, 1H), 8.48 (s, 1H), 8.54(dd, J=9 Hz, J=2.5 Hz, 1H), 8.60 (d, J=4 Hz, 1H), 8.94 (d, J=2 Hz, 1H),9.16 (d, J=2 Hz, 1H), 10.97 (s, 1H), 14.08 (brs, 1H); ESIMS found forC₂₄H₂₂N₆O₂ m/z 427.1 (M+H).

Example 3

Preparation of N,5-di(pyridin-3-yl)-1H-indazole-3-carboxamide (4) isdepicted below in Scheme 29.

Step 1

5-Iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (CXIV)(1.53 g, 4.30 mmol), pyridine-3-boronic acid (CXXXI) (0.58 g, 4.73mmol), and potassium phosphate tribasic (1.37 g, 6.45 mmol) wasdissolved in 1,4-dioxane (43.0 mL) and water (9.0 mL).Tetrakis(triphenylphosphine)palladium(O) (0.50 g, 0.4301 mmol) wasadded, and the reaction was heated to 95° C. for 2.5 h. The solvent wasremoved, and the residue was partitioned between EtOAc and water. Theorganic phase was separated and washed sequentially with water andbrine. The material was dried (MgSO₄), concentrated, and purified byflash chromatography using a 40 g Thomson normal phase silica gelcartridge (100% hexanes→1:1 EtOAc:hexanes) to afford5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde(CXXXII) (0.62 g, 2.02 mmol, 47% yield) as a tan amorphous solid. ¹H NMR(DMSO-d₆) δ ppm 10.23 (s, 1H), 8.95 (d, J=2.3 Hz, 1H), 8.61 (dd, J=4.8,1.5 Hz, 1H), 8.39 (d, J=0.98 Hz, 1H), 8.17-8.14 (m, 1H), 8.06 (d, J=8.8Hz, 1H), 7.95-7.93 (m, 1H), 7.64-7.60 (m, 1H), 6.13 (dd, J=9.4, 2.4 Hz,1H), 3.93-3.90 (m, 1H), 3.86-3.81 (m, 1H), 2.45-2.41 (m, 1H), 2.11-2.07(m, 2H), 1.82-1.78 (m, 1H), 1.66-1.62 (m, 2H); ESIMS found forC₁₈H₁₇N₃O₂ m/z 308 (M+H).

Step 2

To a solution of silver nitrate (0.55 g, 3.25 mmol) in water (10 mL) wasadded a solution of sodium hydroxide (0.26 g, 6.50 mmol) in water (5 mL)to give a brown precipitate.5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde(CXXXII) (0.40 g, 1.30 mmol) dissolved in 1,4-dioxane (3 mL) was addedto the reaction which was stirred at room temperature for 2 h. Thereaction was then extracted with diethyl ether. The aqueous layer wasseparated and carefully brought to pH=3 with 10% aqueous HCl. Theaqueous layer was then extracted five times with iPrOH/chloroform (1/9).The combined organic layers were then dried (MgSO₄) and concentrated toafford5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylicacid (CXXXIII) (0.30 g, 0.93 mmol, 70% yield) as a white solid. ¹H NMR(DMSO-d₆) δ ppm 13.28 (br, 1H), 8.93 (s, 1H), 8.60 (d, J=4.1 Hz, 1H),8.32 (d, J=0.83 Hz, 1H), 8.14-8.12 (m, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.86(dd, J=8.8, 1.7 Hz, 1H), 7.52 (dd, J=7.8, 4.7 Hz, 1H), 6.04 (dd, J=9.3,2.3 Hz, 1H), 3.92-3.90 (m, 1H), 3.83-3.78 (m, 1H), 2.44-2.37 (m, 1H),2.08-2.02 (m, 2H), 1.79-1.76 (m, 1H), 1.63-1.61 (m, 2H).

Step 3

To a solution of5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylicacid (CXXXIII) (0.39 g, 1.21 mmol) and 3-aminopyridine (CXXVII) (0.11 g,1.21 mmol) in DMF (4.0 mL) was added N,N-diisopropylethylamine (0.42 mL,1.21 mmol). The solution was cooled to 0° C. before adding HATU (0.46 g,1.21 mmol). The ice bath was removed, and the reaction warmed to roomtemperature and stirred for 2 h. The DMF was removed under reducedpressure, and the residue was partitioned between chloroform and water.The organic phase was separated and washed sequentially with water andbrine, dried over MgSO₄, filtered, and concentrated. The product waspurified by column chromatography using a 25 g Thomson normal phasesilica gel cartridge (100% CHCl₃→2:98 MeOH:CHCl₃) to affordN,5-di(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide(CXXXIV) (0.36 g, 0.90 mmol, 75% yield) as an off-white solid. ¹H NMR(DMSO-d₆) δ ppm 10.56 (s, 1H), 9.06 (d, J=2.4 Hz, 1H), 8.94 (d, J=2.3Hz, 1H), 8.60 (dd, J=4.8, 1.5 Hz, 1H), 8.47 (d, J=1.1 Hz, 1H), 8.34-8.33(m, 1H), 8.31-8.29 (m, 1H), 8.16-8.14 (m, 1H), 8.04 (d, J=8.8 Hz, 1H),7.90 (dd, J=8.8, 1.8 Hz, 1H), 7.54-7.52 (m, 1H), 7.43-7.41 (m, 1H),7.43-7.41 (m, 1H), 6.08-6.06 (m, 1H), 4.01-3.99 (m, 1H), 3.87-3.82 (m,1H), 2.64-2.57 (m, 1H), 2.11-2.06 (m, 2H), 1.84-1.80 (m, 1H), 1.69-1.65(m, 2H); ESIMS found for C₂₃H₂₁N₅O₂ m/z 400 (M+H).

Step 4

TFA (5.0 mL) was added to a solution ofN,5-di(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide(CXXXIV) (0.36 g, 0.90 mmol) and triethylsilane (0.29 mL, 1.81 mmol) inDCM (5.0 mL). The solution was stirred overnight at room temperature. Anadditional 5.0 mL of TFA was added, and the solution was again stirredovernight. The solvents were removed, and the residue was treated with 7N ammonia in MeOH. The solvents were again removed, and the product waspurified by flash chromatography using a 12 g Thomson normal phasesilica gel cartridge (100% CHCl₃→5:95 MeOH[7N NH₃]:CHCl₃) to affordN,5-di(pyridin-3-yl)-1H-indazole-3-carboxamide (4) (0.23 g, 0.73 mmol,82% yield) as a white solid. ¹H NMR (DMSO-d₆) δ ppm 14.00 (s, 1H), 10.69(s, 1H), 9.08 (d, J=2.0 Hz, 1H), 8.93 (d, J=2.0 Hz, 1H), 8.60 (dd,J=4.8, 1.3 Hz, 1H), 8.48-8.47 (m, 1H), 8.33-8.31 (m, 2H), 8.15-8.12 (m,1H), 7.85-7.81 (m, 2H), 7.54-7.51 (m, 1H), 7.41-7.39 (m, 1H); ESIMSfound for C₁₈H₁₃N₅O m/z 316 (M+H).

The following compounds were prepared in accordance with the proceduredescribed in the above Example 3.

N-(3′-Fluorobiphenyl-3-yl)-5-(pyridin-3-yl)-1H-indazole-3-carboxamide 5

White solid (77 mg, 0.19 mmol, 69% yield). ¹H NMR (DMSO-d₆) δ ppm 13.95(s, 1H), 10.50 (s, 1H), 8.94 (d, J=2.3 Hz, 1H), 8.59 (dd, J=4.6, 1.5 Hz,1H), 8.51 (d, J=1.0 Hz, 1H), 8.31-8.30 (m, 1H), 8.15-8.13 (m, 1H),7.99-7.97 (m, 1H), 7.83-7.82 (m, 2H), 7.55-7.45 (m, 6H), 7.24-7.22 (m,1H); ESIMS found for C₂₅H₁₇FN₄O m/z 409 (M+H).

5-(Pyridin-3-yl)-N-(pyridin-4-yl)-1H-indazole-3-carboxamide 6

Off-white solid (52 mg, 0.16 mmol, 77% yield). ¹H NMR (DMSO-d₆) δ ppm14.05 (br, 1H), 10.83 (s, 1H), 8.94 (d, J=2.0 Hz, 1H), 8.60 (dd, J=4.6,1.2 Hz, 1H), 8.48-8.47 (m, 3H), 8.15-8.13 (m, 1H), 7.94 (dd, J=5.0, 1.4Hz, 2H), 7.86-7.82 (m, 2H), 7.54-7.52 (m, 1H); ESIMS found for C₁₈H₁₃N₅Om/z 316 (M+H).

N-(5-((Dimethylamino)methyl)pyridin-3-yl)-5-(pyridin-3-yl)-1H-indazole-3-carboxamide7

Off-white solid (37 mg, 0.10 mmol, 47% yield). ¹H NMR (DMSO-d₆) δ ppm14.00 (s, 1H), 10.68 (s, 1H), 8.94 (d, J=2.0 Hz, 1H), 8.91 (d, J=2.3 Hz,1H), 8.60 (dd, J=4.7, 1.2 Hz, 1H), 8.49-8.48 (m, 1H), 8.38-8.37 (m, 1H),8.21 (d, J=2.2 Hz, 1H), 8.16-8.13 (m, 1H), 7.85-7.81 (m, 2H), 7.52 (dd,J=7.9, 4.9 Hz, 1H), 3.44 (s, 2H), 2.19 (s, 6H); ESIMS found forC₂₁H₂₀N₆O m/z 373 (M+H).

5-(Pyridin-3-yl)-N-(6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide8

Off-white solid (38 mg, 0.10 mmol, 77% yield). ¹H NMR (DMSO-d₆) δ ppm13.99 (br, 1H), 10.64 (s, 1H), 8.96 (d, J=2.5 Hz, 1H), 8.93 (d, J=2.4Hz, 1H), 8.59 (dd, J=4.8, 1.5 Hz, 1H), 8.48 (d, J=1.2 Hz, 1H), 8.27 (dd,J=8.5, 2.5 Hz, 1H), 8.16-8.12 (m, 1H), 7.84-7.80 (m, 2H), 7.54-7.51 (m,1H), 7.41 (d, J=8.5 Hz, 1H), 2.37 (s, 2H), 2.50-2.47 (m, 4H), 1.72-1.70(m, 4H); ESIMS found for C₂₃H₂₂N₆O m/z 399 (M+H).

N-(5-(3-Fluorophenyl)pyridin-3-yl)-5-(pyridin-3-yl)-1H-indazole-3-carboxamide9

White solid (35 mg, 0.09 mmol, 47% yield). ¹H NMR (DMSO-d₆) δ ppm 14.05(br s, 1H), 10.79 (s, 1H), 9.13 (d, J=2.0 Hz, 1H), 8.94 (d, J=1.9 Hz,1H), 8.68-8.65 (m, 2H), 8.60 (dd, J=4.83, 4.83 Hz, 1H), 8.52-8.49 (m,1H), 8.16-8.12 (m, 1H), 7.85-7.81 (m, 2H), 7.62-7.56 (m, 3H), 7.54-7.50(m, 1H), 7.31-7.26 (m, 1H). ESIMS found for C₂₄H₁₆FN₅O m/z 410.5 (M+H).

N-(2-(4-Methylpiperazin-1-yl)pyridin-3-yl)-5-(pyridin-3-yl)-1H-indazole-3-carboxamide11

White solid (11 mg, 0.03 mmol, 65% yield). ¹H NMR (DMSO-d₆) δ ppm 14.10(s, 1H), 9.63 (s, 1H), 8.93 (d, J=2.1 Hz, 1H), 8.65-8.59 (m, 2H), 8.48(s, 1H), 8.16-8.12 (m, 1H), 8.11-8.09 (m, 1H), 7.87-7.80 (m, 2H),7.55-7.51 (m, 1H), 7.20-7.17 (m, 1H), 3.10-3.06 (m, 4H), 2.80-2.40 (m,4H), 2.30 (s, 3H). ESIMS found for C₂₃H₂₃N₇O m/z 414.0 (M+H).

N-(6-(4-Methylpiperazin-1-yl)pyridin-3-yl)-5-(pyridin-3-yl)-1H-indazole-3-carboxamide12

White solid (31 mg, 0.07 mmol, 39% yield). ¹H NMR (DMSO-d₆) δ ppm 13.86(br s, 1H), 10.33 (s, 1H), 8.92 (d, J=2.1 Hz, 1H), 8.60-8.58 (m, 2H),8.46 (s, 1H), 8.14-8.11 (m, 1H), 8.10-8.02 (m, 1H), 7.83-7.78 (m, 2H),7.54-7.50 (m, 1H), 6.86 (d, J=9.1 Hz, 1H), 3.45-3.42 (m, 4H), 2.42-2.39(m, 4H), 2.21 (s, 3H). ESIMS found for C₂₃H₂₃N₇O m/z 414.3 (M+H).

N-(Pyridazin-4-yl)-5-(pyridin-3-yl)-1H-indazole-3-carboxamide 14

Off-white solid (50 mg, 0.16 mmol, 99% yield). ¹H NMR (DMSO-d₆) δ ppm14.20-13.90 (br, 1H), 11.15 (s, 1H), 9.71-9.70 (m, 1H), 9.09-9.08 (m,1H), 8.94 (d, J=2.0 Hz, 1H), 8.61-8.60 (m, 1H), 8.47-8.46 (m, 1H), 8.25(dd, J=5.9, 2.8 Hz, 1H), 8.16-8.13 (m, 1H), 7.86-7.85 (m, 2H), 7.53 (dd,J=7.8, 5.0 Hz, 1H); ESIMS found for C₁₇H₁₂N₆O m/z 317 (M+H).

N-(6-((4-Methylpiperazin-1-yl)methyl)pyridin-3-yl)-5-(pyridin-3-yl)-1H-indazole-3-carboxamide15

White solid (42 mg, 0.10 mmol, 81% yield). ¹H NMR (DMSO-d₆) δ ppm 13.97(br, 1H), 10.65 (s, 1H), 8.97 (d, J=2.4 Hz, 1H), 8.93 (d, J=2.1 Hz, 1H),8.59 (dd, J=4.7, 1.5 Hz, 1H), 8.48-8.47 (m, 1H), 8.28 (dd, J=8.5, 2.5Hz, 1H), 8.15-8.12 (m, 1H), 7.85-7.81 (m, 2H), 7.54-7.51 (m, 1H), 7.40(d, J=8.5 Hz, 1H), 3.55 (s, 2H), 2.42-2.28 (m, 8H), 2.15 (s, 3); ESIMSfound for C₂₄H₂₅N₇O m/z 428 (M+H).

Example 4

Preparation of5-(5-fluoropyridin-3-yl)-N-(pyridin-3-yl)-1H-indazole-3-carboxamide (13)is depicted below in Scheme 30.

Step 1

To a stirring solution of 3-aminopyridine (CXXV) (0.195 g, 0.2.07 mmol)in DMF (10 mL) was added 5-bromo-1H-indazole-3-carboxylic acid (CXV)(0.500 g, 0.2.07 mmol) and N,N-diisopropylethylamine (0.723 mL, 4.15mmol). The reaction mixture was cooled to 0° C. and added with HATU(0.787 g, 2.07 mmol). The reaction mixture was allowed to warm to roomtemperature and stirred for an additional 2 h. The solution wasconcentrated under vacuum. The residue was purified by columnchromatography (1:99 MeOH[7N Mb]: CHCl₃ 4:96 MeOH[7N Mb]: CHCl₃) toafford 5-bromo-N-(pyridin-3-yl)-1H-indazole-3-carboxamide (CXXXV) (0.200g, 0.63 mmol, 30% yield) as a white solid. ESIMS found for C₁₃H₉BrN₄Om/z 318.0 (M+H).

Step 2

To a microwave vial was added5-bromo-N-(pyridin-3-yl)-1H-indazole-3-carboxamide (CXXXV) (0.200 g,0.63 mmol), 5-fluoropyridine-3-boronic acid (CXXIX) (0.098 g, 0.694mmol), tetrakis(triphenylphosphine)palladium(O) (0.036 g, 0.032 mmol),potassium phosphate (0.201 g, 0.947 mmol), water (1 mL), and DMF (5 mL).The reaction vial was capped, purged with argon and heated undermicrowave irradiation for 1 h at 180° C. The solution was filteredthrough a pad of Celite and concentrated under vacuum. The crude productwas purified by column chromatography (100% CHCl₃→2:98 MeOH[7N NH₃]:CHCl₃) to afford5-(5-fluoropyridin-3-yl)-N-(pyridin-3-yl)-1H-indazole-3-carboxamide (13)(4 mg, 0.01 mmol, 2% yield) as a white solid. ¹H NMR (DMSO-d₆) δ ppm14.02 (br s, 1H), 10.70 (s, 1H), 9.08 (d, J=2.5 Hz, 1H), 8.83 (t, J=1.8Hz, 1H), 8.60 (d, J=2.7 Hz, 1H), 8.53-8.52 (m, 1H), 8.34-8.29 (m, 2H),8.14-8.09 (m, 1H), 7.89-7.81 (m, 2H), 7.42-7.38 (m, 1H). ESIMS found forC₁₈H₁₂FN₅O m/z 334.0 (M+H).

Example 5

Preparation ofN-(pyridin-3-yl)-5-(5-(trifluoromethyl)pyridin-3-yl)-1H-indazole-3-carboxamide(16) is depicted below in Scheme 31.

Step 1

Preparation of intermediate5-bromo-N-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide(CXXXV) was performed following the procedure listed in Scheme 19, Step4. Light yellow solid (5.5 g, 13.7 mmol, 88% yield). ESIMS found forC₁₈H₁₇BrN₄O₂ m/z 401.1 (M^(79Br)+H) and 403.1 (M^(81Br)+H).

Steps 2-3

Preparation of intermediateN-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-5-(5-(trifluoromethyl)pyridin-3-yl)-1H-indazole-3-carboxamide(CXXXVIII) was performed following the procedure listed in Scheme 26,Steps 1-2. Tan solid (295 mg, 0.63 mmol, 84% yield). ESIMS found forC₂₄H₂₀F₃N₅O₂ m/z 468.1 (M+H).

Step 4

Preparation ofN-(pyridin-3-yl)-5-(5-(trifluoromethyl)pyridin-3-yl)-1H-indazole-3-carboxamide(16) was performed following the procedure listed in Scheme 28, Step 4.White solid (95 mg, 0.25 mmol, 39.3% yield). ¹H NMR (DMSO-d₆) δ ppm 7.40(dd, J=2.2 Hz, J=2 Hz, 1H), 7.84 (d, J=6.7 Hz, 1H), 7.93 (dd, J=1.5 Hz,J=7 Hz, 1H), 8.29-8.34 (m, 2H), 8.50 (s, 1H), 8.57 (s, 1H), 8.99 (s,1H), 9.09 (d, J=2 Hz, 1H), 9.25 (d, J=1.6 Hz, 1H), 10.72 (brs, 1H);ESIMS found for C₁₉H₁₂F₃N₅O m/z 383.9 (M+H).

The following compounds were prepared in accordance with the proceduredescribed in the above Example 5,

5-(5-((Dimethylamino)methyl)pyridin-3-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-1H-indazole-3-carboxamide 26

White solid (93 mg, 0.21 mmol, 78% yield). ¹H NMR (DMSO-d₆) δ ppm 2.24(s, 6H), 3.57 (s, 2H), 7.86 (Abq, J=8 Hz, 2H), 7.93 (d, J=9 Hz, 1H),8.04 (brs, 1H), 8.50 (d, J=7 Hz, 1H), 8.63 (dd, J=9 Hz, J=2 Hz, 1H),8.85 (d, J=2 Hz, 1H), 9.27 (d, J=2 Hz, 1H), 11.11 (s, 1H), 14.11 (s,1H); ESIMS found for C₂₂H₁₉F₃N₆O m/z 441.0 (M+H)

N-(5-(3-(Pyridin-3-ylcarbamoyl)-1H-indazol-5-yl)pyridin-3-yl)morpholine-4-carboxamide 32

White solid (132 mg, 0.30 mmol, 56% yield). ¹H NMR (DMSO-d₆) δ ppm 3.49(t, J=5 Hz, 4H), 3.64 (t, J=5 Hz, 4H), 7.40 (dd, J=8 Hz, J=5 Hz, 1H),7.82 (d, J=1 Hz, 1H), 8.26 (t, J=2 Hz, 1H), 8.30-8.34 (m, 2H), 8.47 (s,1H), 8.54 (d, J=2 Hz, 1H), 8.72 (d, J=2 Hz, 1H), 8.87 (s, 1H), 9.09 (d,2 Hz, 1H), 10.71 (s, 1H), 14.01 (s, 1H); ESIMS found for C₂₃H₂₁N₇O₃ m/z444.3 (M+H).

5-(5-((Dimethylamino)methyl)pyridin-3-yl)-N-(6-(2-fluorophenoxy)pyridin-3-yl)-1H-indazole-3-carboxamide 36

White solid (137 mg, 0.28 mmol, 53% yield). ¹H NMR (DMSO-d₆) δ ppm 2.20(s, 6H), 3.53 (s, 2H), 7.16 (d, J=9 Hz, 1H), 7.22-7.40 (m, 4H), 7.82(d/Abq, J=9 Hz, J=1 Hz, 2H), 8.00 (t, J=2 Hz, 1H), 8.38 (dd, J=9 Hz, J=3Hz, 1H), 8.47 (s, 1H), 8.49 (d, J=2 Hz, 1H), 8.55 (d, J=3 Hz, 1H), 8.83(d, J=2 Hz, 1H), 10.67 (s, 1H), 13.97 (brs, 1H); ESIMS found forC₂₇H₂₃FN₆O₂ m/z 383.1 (M+H).

5-(5-(Cyclopropanecarboxamido)pyridin-3-yl)-N-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indazole-3-carboxamide38

White solid (39 mg, 0.08 mmol, 61% yield). ¹H NMR (DMSO-d₆) δ ppm0.83-0.90 (m, 4H), 1.80-1.86 (m, 1H), 2.25 (brs, 3H), 2.45 (brs, 4H),3.45 (brs, 4H), 6.86 (d, J=9 Hz, 1H), 7.79 (d, J=1 Hz, 1H), 8.04 (dd,J=9 Hz, J=3 Hz, 1H), 8.42 (t, J=2 Hz, 1H), 8.46 (s, 1H), 8.60 (dd, J=10Hz, J=3 Hz, 2H), 8.76 (d, J=2 Hz, 1H), 10.34 (s, 1H), 10.56 (s, 1H),13.90 (s, 1H); ESIMS found for C₂₇H₂₇N₈O₂ m/z 497.4 (M+H).

5-(5-(Cyclopropanecarboxamido)pyridin-3-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-1H-indazole-3-carboxamide 39

White solid (128 mg, 0.27 mmol, 45% yield). ¹H NMR (DMSO-d₆) δ ppm0.82-0.90 (m, 4H), 1.80-1.86 (m, 1H), 7.84 (s, 2H0, 7.92 (d, J=9 Hz,1H), 8.43 (d, J=2 Hz, 1H), 8.48 (s, 1H), 8.61-8.65 (m, 2H), 8.77 (d, J=2Hz, 1H), 9.27 (d, J=2 Hz, 1H), 10.57 (s, 1H), 11.11 (s, 1H), 14.11 (s,1H); ESIMS found for C₂₃H₁₇F₃N₆O₂ m/z 467.1 (M+H).

5-(5-((Dimethylamino)methyl)pyridin-3-yl)-N-(pyridin-3-yl)-1H-indazole-3-carboxamide40

White solid (312 mg, 0.84 mmol, 77% yield). ¹H NMR (DMSO-d₆) δ ppm 2.21(s, 6H), 3.53 (s, 2H), 7.40 (dd, J=8 Hz, J=5 Hz, 1H), 7.83 (d/Abq, J=9Hz, J=2 Hz, 2H), 8.01 (t, J=2 Hz, 1H), 8.29-8.34 (m, 2H), 8.48 (dd, J=4Hz, J=1 Hz, 1H), 8.83 (d, J=2 Hz, 1H), 9.08 (d, J=3 Hz, 1H), 10.70 (s,1H), 13.99 (brs, 1H); ESIMS found for C₂₁H₂₀N₆O m/z 373.0 (M+H).

5-(5-(Cyclopropanecarboxamido)pyridin-3-yl)-N-(pyridin-3-yl)-1H-indazole-3-carboxamide41

White solid (148 mg, 0.37 mmol, 71% yield). ¹H NMR (DMSO-d₆) δ ppm0.83-0.90 (m, 4H), 1.80-1.87 (m, 1H), 7.40 (dd, J=8 Hz, J=5 Hz, 1H),7.82 (d, J=1 Hz, 1H), 8.29-8.34 (m, 2H), 8.43 (t, J=2 Hz, 1H), 8.47 (s,1H), 8.62 (d, J=2 Hz, 1H), 8.76 (d, J=2 Hz, 1H), 9.08 (d, J=2 Hz, 1H),10.57 (s, 1H), 10.70 (s, 1H), 14.01 (s, 1H); ESIMS found for C₂₂H₁₈N₆O₂m/z 399.0 (M+H).

N-(Pyridin-3-yl)-5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide43

White solid (157 mg, 0.39 mmol, 76% yield). ¹H NMR (DMSO-d₆) δ ppm1.70-1.74 (m, 4H), 2.46-2.52 (m, 4H), 3.71 (s, 2H), 7.40 (dd, J=8 Hz,J=5 Hz, 1H), 7.83 (d/Abq, J=9 Hz, J=2 Hz, 2H), 8.02 (t, J=2 Hz, 1H),8.29-8.34 (m, 2H), 8.48 (s, 1H), 8.51 (d, J=2 Hz, 1H), 8.82 (d, J=2 Hz,1H), 9.08 (d, J=2 Hz, 1H), 10.70 (s, 1H), 14.00 (s, 1H); ESIMS found forC₂₃H₂₂N₆O m/z 399.0 (M+H).

N-(6-Ethoxypyridin-3-yl)-5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide44

White solid (62 mg, 0.14 mmol, 39% yield). ¹H NMR (DMSO-d₆) δ ppm 1.32(t, J=7 Hz, 3H), 1.70-1.74 (m, 4H), 2.47-2.52 (m, 4H), 3.71 (s, 2H),4.29 (q, J=7 Hz, 2H), 6.81 (d, J=9 Hz, 1H), 7.82 (d/Abq, J=9 Hz, J=2 Hz,2H), 8.01 (t, J=2 Hz, 1H), 8.16 (dd, J=9 Hz, J=3 Hz, 1H), 8.46 (s, 1H),8.51 (d, J=2 Hz, 1H), 8.63 (d, J=2 Hz, 1H), 8.81 (d, J=2 Hz, 1H), 10.51(s, 1H), 13.94 (brs, 1H); ESIMS found for C₂₅H₂₆N₆O₂ m/z 443.4 (M+H).

N-(6-Ethoxypyridin-3-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide45

White solid (98 mg, 0.21 mmol, 44% yield). ¹H NMR (DMSO-d₆) δ ppm 1.32(t, J=7 Hz, 3H), 1.34-1.42 (m, 2H), 1.47-1.53 (m, 4H), 2.38 (brs, 4H),3.56 (s, 2H), 4.29 (q, J=7 Hz, 2H), 6.81 (d, J=9 Hz, 1H), 7.81 (d/Abq,J=9 Hz, J=2 Hz, 2H), 7.99 (t, J=2 Hz, 1H), 8.16 (dd, J=9 Hz, J=3 Hz,1H), 8.46 (d, J=1 Hz, 1H), 8.49 (d, J=2 Hz, 1H), 8.63 (d, J=2 Hz, 1H),8.81 (d, J=2 Hz, 1H), 10.51 (s, 1H), 13.92 (brs, 1H); ESIMS found forC₂₆H₂₈N₆O₂ m/z 457.3 (M+H).

5-(5-(Piperidin-1-ylmethyl)pyridin-3-yl)-N-(pyridin-3-yl)-1H-indazole-3-carboxamide46

White solid (126 mg, 0.31 mmol, 52% yield). ¹H NMR (DMSO-d₆) δ ppm1.36-1.42 (m, 2H), 1.48-1.55 (m, 4H), 2.39 (brs, 4H), 3.57 (s, 2H), 7.40(dd, J=8 Hz, J=5 Hz, 1H), 7.83 (d/Abq, J=9 Hz, J=2 Hz, 2H), 7.99 (t, J=2Hz, 1H), 8.30-8.34 (m, 2H), 8.48 (d, J=1 Hz, 1H), 8.49 (d, J=2 Hz, 1H),8.82 (d, J=2 Hz, 1H), 9.08 (d, J=2 Hz, 1H), 10.70 (s, 1H), 14.00 (brs,1H); ESIMS found for C₂₄H₂₄N₆O m/z 413.0 (M+H).

5-(5-(Piperidin-1-ylmethyl)pyridin-3-yl)-N-(4-(trifluoromethyl)pyridin-3-yl)-1H-indazole-3-carboxamide 47

White solid (150 mg, 0.31 mmol, 71% yield). ¹H NMR (DMSO-d₆) δ ppm1.34-1.42 (m, 2H), 1.46-1.53 (m, 4H), 2.37 (brs, 4H), 3.55 (s, 2H),7.81-7.87 (m, 3H), 7.98 (s, 1H), 8.41 (s, 1H), 8.48 (d, J=2 Hz, 1H),8.75 (d, J=5 Hz, 1H), 8.80 (d, J=2 Hz, 1H), 9.07 (s, 1H), 10.22 (s, 1H),14.06 (brs, 1H); ESIMS found for C₂₅H₂₃F₃N₆O m/z 481.0 (M+H).

N-(Pyridin-3-yl)-5-(3-(pyrrolidin-1-ylmethyl)phenyl)-1H-indazole-3-carboxamide49

Tan amorphous solid (53.4 mg, 0.13 mmol, 72% yield). ¹H NMR (DMSO-d₆) δppm 1.70-1.71 (m, 4H), 2.47-2.49 (m, 4H), 3.67 (s, 2H), 7.31 (d, J=8 Hz,1H), 7.40 (dd, J=8 Hz, J=5 Hz, 1H), 7.44 (t, J=8 Hz, 1H), 7.58-7.60 (m,1H), 7.63-7.64 (m, 1H), 7.76-7.78 (m, 2H), 8.30-8.34 (m, 2H), 8.44 (s,1H), 9.08 (d, J=2 Hz, 1H), 10.68 (s, 1H), 13.93 (s, 1H); ESMS found forC₂₄H₂₃N₅O m/z 398 (M+H).

N-(6-Phenylpyridin-3-yl)-5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide50

Tan flaky solid (61.3 mg, 0.13 mmol, 74% yield). ¹H NMR (DMSO-d₆) δ ppm1.71-1.72 (m, 4H), 3.72 (s, 2H), 7.39-7.42 (m, 1H), 7.47-7.50 (m, 2H),7.81-7.86 (m, 2H), 8.00 (d, J=9 Hz, 1H), 8.02-8.03 (m, 1H), 8.08-8.10(m, 2H), 8.45 (dd, J=9 Hz, J=3 Hz, 1H), 8.49-8.50 (m, 1H), 8.51 (d, J=2Hz, 1H), 8.83 (d, J=2 Hz, 1H), 9.18 (d, J=3 Hz, 1H), 10.81 (s, 1H),14.03 (s, 1H); ESIMS found for C₂₉H₂₆N₆O m/z 475 (M+H).

N-(Pyridin-3-yl)-5-(6-(pyrrolidin-1-yl)pyridin-3-yl)-1H-indazole-3-carboxamide51

Yellow solid (32 mg, 0.08 mmol, 37.8% yield). ¹H NMR (DMSO-d₆) δ ppm1.94-2.01 (m, 4H), 3.42-3.48 (m, 4H), 6.57 (d, J=9 Hz, 1H), 7.40 (dd,J=8 Hz, J=5 Hz, 1H), 7.72 (d, J=1 Hz, 2H), 7.85 (dd, J=9 Hz, J=3 Hz,1H), 8.29-8.34 (m, 3H), 8.43 (d, J=2 Hz, 1H), 9.08 (d, J=2 Hz, 1H),10.63 (s, 1H), 13.87 (s, 1H); ESIMS found for C₂₂H₂₀N₆O m/z 385.0 (M+H).

N-(6-Cyanopyridin-3-yl)-5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide52

Beige solid (52 mg, 0.12 mmol, 49.1% yield). ¹H NMR (DMSO-d₆) δ ppm1.70-1.75 (m, 4H), 3.31-3.36 (m, 4H), 7.85 (dq, J=9 Hz, J=2 Hz, 2H),8.02 (s, 1H), 8.05 (d, J=9 Hz, 1H), 8.47 (s, 1H), 8.52 (d, J=2 Hz, 1H),8.58 (dd, J=9 Hz, J=3 Hz, 1H), 8.82 (d, J=2 Hz, 1H), 9.28 (d, J=2 Hz,1H), 11.18 (s, 1H), 14.13 (brs, 1H); ESIMS found for C₂₄H₂₁N₇O m/z 424.3(M+H).

5-(6-Methoxypyridin-3-yl)-N-(pyridin-3-yl)-1H-indazole-3-carboxamide 54

White solid (79.7 mg, 0.23 mmol, 44.2% yield). ¹H NMR (DMSO-d₆) δ ppm3.91 (s, 3H), 6.95 (d, J=9 Hz, 1H), 7.40 (dd, J=9 Hz, J=5 Hz, 1H), 7.78(dd, J=11 Hz, J=2 Hz, 2H), 8.06 (dd, J=9 Hz, J=3 Hz, 1H), 8.29-8.34 (m,2H), 8.39 (s, 1H), 8.51 (d, J=2 Hz, 1H), 9.08 (d, J=3 Hz, 1H), 10.67 (s,1H), 13.91 (brs, 1H); ESIMS found for C₁₉H₁₅N₅O₂ m/z 346.0 (M+H).

5-(5-Benzylpyridin-3-yl)-N-(pyridin-3-yl)-1H-indazole-3-carboxamide 55

Yellow solid (101.9 mg, 0.25 mmol, 76% yield). ¹H NMR (DMSO-d₆) δ ppm4.09 (s, 2H), 7.19-7.23 (m, 1H), 7.30-7.35 (m, 4H), 7.39-7.41 (m, 1H),7.78-7.82 (m, 2H), 7.99 (t, J=2 Hz, 1H), 8.31-8.33 (m, 2H), 8.45 (s,1H), 8.51 (d, J=2 Hz, 1H), 8.76 (d, J=2 Hz, 1H), 9.08 (d, J=2 Hz, 1H),10.69 (s, 1H), 14.00 (s, 1H); ESIMS found for C₂₅H₁₉N₅O m/z 406 (M+H).

5-(5-Phenoxypyridin-3-yl)-N-(pyridin-3-yl)-1H-indazole-3-carboxamide 56

White solid (73.6 mg, 0.18 mmol, 75% yield). ¹H NMR (DMSO-d₆) δ ppm7.17-7.18 (m, 2H), 7.22-7.23 (m, 1H), 7.38-7.41 (m, 1H), 7.44-7.47 (m,2H), 7.72-7.73 (m, 1H), 7.80-7.81 (m, 2H), 8.29-8.31 (m, 2H), 8.37-8.38(m, 1H), 8.44-8.45 (m, 1H), 8.74 (d, J=2 Hz, 1H), 9.06 (d, J=2 Hz, 1H),10.69 (s, 1H), 14.00 (s, 1H); ESIMS found for C₂₄H₁₇N₅O₂ m/z 408 (M+H).

5-(5-(Pyrrolidin-1-ylmethyl)pyridin-3-yl)-N-(4-(trifluoromethyl)pyridin-3-yl)-1H-indazole-3-carboxamide 57

White solid (64 mg, 0.14 mmol, 35.2% yield). ¹H NMR (DMSO-d₆) δ ppm1.67-1.74 (m, 4H), 2.44-2.52 (m, 4H), 3.70 (s, 2H), 7.81-7.88 (m, 3H),8.00 (d, J=2 Hz, 1H), 8.41 (s, 1H), 8.50 (d, J=2 Hz, 1H), 8.75 (d, J=5Hz, 1H), 8.81 (d, J=2 Hz, 1H), 9.07 (s, 1H), 10.22 (s, 1H), 14.01 (brs,1H); ESIMS found for C₂₄H₂₁F₃N₆O m/z 467.3 (M+H).

5-(5-(Cyclohexylcarbamoyl)pyridin-3-yl)-N-(pyridin-3-yl)-1H-indazole-3-carboxamide59

Light brown solid (117 mg, 0.27 mmol, 49.7% yield). ¹H NMR (DMSO-d₆) δppm 1.10-1.21 (m, 1H), 1.28-1.39 (m, 4H), 1.63 (d, J=12 Hz, 1H),1.72-1.78 (m, 2H), 1.86-1.91 (m, 2H), 3.77-3.87 (m, 1H), 7.41 (dd, J=8Hz, J=5 Hz, 1H), 7.84 (d, J=8 Hz, 1H), 7.91 (d, J=9 Hz, 1H), 8.30-8.36(m, 2H), 8.48 (t, J=2 Hz, 1H), 8.55 (s, 1H), 8.59 (d, J=8 Hz, 1H), 8.99(d, J=2 Hz, 1H), 9.04 (d, J=2 Hz, 1H), 9.09 (d, J=2 Hz, 1H), 10.72 (s,1H), 14.04 (s, 1H); ESIMS found for C₂₅H₂₄N₆O₂ m/z 441.0 (M+H).

5-(3-Fluoro-5-((4-methylpiperazin-1-yl)methyl)phenyl)-N-(4-(trifluoromethyl)pyridin-3-yl)-1H-indazole-3-carboxamide60

White solid (43 mg, 0.08 mmol, 76.3% yield). ¹H NMR (DMSO-d₆) δ ppm 1.23(s, 3H), 2.22-2.50 (m, 8H), 3.56 (s, 2H), 7.12 (d, J=9 Hz, 1H), 7.42(dd, J=8 Hz, J=2 Hz, 1H), 7.47 (s, 1H), 7.80 (d, J=1 Hz, 2H), 7.85 (d,J=5 Hz, 1H), 8.39 (s, 1H), 8.75 (d, J=5 Hz, 1H), 9.08 (s, 1H), 10.22 (s,1H), 14.02 (brs, 1H); ESIMS found for C₂₆H₂₄F₄N₆O m/z 513.3 (M+H).

5-(5-((4-Methylpiperazin-1-yl)methyl)pyridin-3-yl)-N-(pyridin-3-yl)-1H-indazole-3-carboxamide61

White solid (81.6 mg, 0.19 mmol, 55% yield). ¹H NMR (DMSO-d₆) δ ppm 2.14(s, 3H), 2.33-2.42 (m, 8H), 3.60 (s, 2H), 7.39-7.41 (m, 1H), 7.81-7.85(m, 2H), 8.00-8.01 (m, 1H), 8.31-8.33 (m, 2H), 8.47-8.48 (m, 1H), 8.49(d, J=2 Hz, 1H), 8.82 (d, J=2 Hz, 1H), 9.08 (d, J=3 Hz, 1H), 10.74 (s,1H), 14.00 (s, 1H); ESIMS found for C₂₄H₂₅N₇O m/z 427.8 (M+H).

N-(6-Cyanopyridin-3-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide62

Off-white solid (42 mg, 0.10 mmol, 36.9% yield). ¹H NMR (DMSO-d₆) δ ppm1.36-1.42 (m, 2H), 1.47-1.54 (m, 4H), 2.38 (brs, 4H), 3.57 (s, 2H), 7.85(d, J=1 Hz, 2H), 8.00 (t, J=2 Hz, 1H), 8.05 (d, J=9 Hz, 1H), 8.47 (d,J=1 Hz, 1H), 8.50 (d, J=2 Hz, 1H), 8.58 (dd, J=9 Hz, J=3 Hz, 1H), 8.82(d, J=2 Hz, 1H), 9.28 (d, J=2 Hz, 1H), 11.18 (s, 1H), 14.12 (brs, 1H);ESIMS found for C₂₅H₂₃N₇O m/z 438.1 (M+H).

5-(5-(Piperidin-1-ylmethyl)pyridin-3-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-1H-indazole-3-carboxamide 63

White solid (78 mg, 0.16 mmol, 49% yield). ¹H NMR (DMSO-d₆) δ ppm1.35-1.44 (m, 2H), 1.46-1.57 (m, 4H), 2.40 (brs, 4H), 3.59 (brs, 2H),7.85 (s, 2H), 7.93 (d, J=9 Hz, 1H), 8.01 (s, 1H), 8.48 (s, 1H), 8.50 (s,1H), 8.63 (d, J=8 Hz, 1H), 8.83 (s, 1H), 9.27 (s, 1H), 11.11 (s, 1H),14.11 (brs, 1H); ESIMS found for C₂₅H₂₃F₃N₆O m/z 481.1 (M+H).

5-(5-(Morpholinomethyl)pyridin-3-yl)-N-(pyridin-3-yl)-1H-indazole-3-carboxamide64

White solid (77 mg, 0.19 mmol, 66% yield). ¹H NMR (DMSO-d₆) δ ppm2.41-2.43 (m, 4H), 3.58-3.60 (m, 4H), 3.61 (s, 2H), 7.39-7.41 (m, 1H),7.81-7.85 (m, 2H), 8.02-8.03 (m, 1H), 8.31-8.33 (m, 2H), 8.47-8.48 (m,1H), 8.51 (d, J=2 Hz, 1H), 8.83 (d, J=2 Hz, 1H), 9.08 (d, J=2 Hz, 1H),10.70 (s, 1H), 14.00 (s, 1H); ESIMS found for C₂₃H₂₂N₆O₂ m/z 415 (M+H).

N-(6-Phenylpyridin-3-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide65

White solid (61.5 mg, 0.13 mmol, 68% yield). ¹H NMR (DMSO-d₆) δ ppm1.39-1.40 (m, 2H), 1.49-1.53 (m, 4H), 2.38-2.39 (m, 4H), 3.57 (s, 2H),7.39-7.43 (m, 1H), 7.47-7.50 (m, 2H), 7.82-7.86 (m, 2H), 7.99-8.01 (m,2H), 8.08-8.10 (m, 2H), 8.44 (dd, J=9 Hz, J=3 Hz, 1H), 8.50-8.51 (m,2H), 8.83 (d, J=2 Hz, 1H), 9.18 (d, J=3 Hz, 1H), 10.81 (s, 1H), 14.02(s, 1H); ESIMS found for C₃₀H₂₈N₆O m/z 489 (M+H).

5-(5-Cyanopyridin-3-yl)-N-(pyridin-3-yl)-1H-indazole-3-carboxamide 66

Beige solid (107 mg, 0.31 mmol, 66.7% yield). ¹H NMR (DMSO-d₆) δ ppm7.40 (dd, J=8 Hz, J=4 Hz, 1H), 7.84 (d, J=8 Hz, 1H), 7.91 (dd, J=9 Hz,J=2 Hz, 1H), 8.30-8.34 (m, 2H), 8.57 (s, 1H), 8.72 (t, J=2 Hz, 1H), 9.03(d, J=2 Hz, 1H), 9.09 (d, J=2 Hz, 1H), 9.23 (d, J=2 Hz, 1H), 10.72 (s,1H), 14.06 (s, 1H); ESIMS found for C₁₉H₁₂N₆O m/z 340.8 (M+H).

5-(3-Fluoro-5-(piperidin-1-ylmethyl)phenyl)-N-(pyridin-3-yl)-1H-indazole-3-carboxamide67

Yellow solid (84 mg, 0.20 mmol, 66% yield). ¹H NMR (DMSO-d₆) δ ppm1.37-1.39 (m, 2H), 1.49-1.54 (m, 4H), 2.37-2.38 (m, 4H), 3.54 (s, 2H),7.12-7.13 (m, 1H), 7.39-7.43 (m, 2H), 7.47-7.48 (m, 1H), 7.77-7.81 (m,2H), 8.31-8.33 (m, 2H), 8.44-8.45 (m, 1H), 9.08 (d, J=2 Hz, 1H), 10.69(s, 1H), 13.97 (s, 1H); ESIMS found for C₂₅H₂₄FN₅O m/z 430 (M+H).

5-(5-(Morpholinomethyl)pyridin-3-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-1H-indazole-3-carboxamide68

White solid (72 mg, 0.15 mmol, 30.5% yield). ¹H NMR (DMSO-d₆) δ ppm 2.43(brs, 4H), 3.56-3.63 (m, 4H), 3.62 (s, 2H), 7.85 (Abq, J=9 Hz, 2H), 7.93(d, J=9 Hz, 1H), 8.04 (s, 1H), 8.49 (s, 1H), 8.52 (d, J=1 Hz, 1H), 8.63(dd, J=9 Hz, J=3 Hz, 1H), 8.84 (d, J=2 Hz, 1H), 9.27 (d, J=2 Hz, 1H),11.11 (s, 1H), 14.11 (brs, 1H); ESIMS found for C₂₄H₂₁F₃N₆O₂ m/z 483.3(M+H).

N-(6-Morpholinopyridin-3-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide69

Light yellow solid (58 mg, 0.12 mmol, 36.4% yield). ¹H NMR (DMSO-d₆) δppm 1.37-1.44 (m, 2H), 1.51 (quin, J=5 Hz, 4H), 2.33-2.40 (m, 4H), 3.40(t, J=5 Hz, 4H), 3.56 (s, 2H), 3.71 (t, 5 Hz, 4H), 6.89 (d, J=9 Hz, 1H),7.78 (d, J=8 Hz, 1H), 7.81 (d, J=9 Hz, 1H), 7.97 (t, J=2 Hz, 1H), 8.06(dd, J=9 Hz, J=2 Hz, 1H), 8.46 (d, J=10 Hz, 1H), 8.60 (d, J=2 Hz, 1H),8.79 (d, J=2 Hz, 1H), 10.35 (s, 1H), 13.90 (brs, 1H); ESIMS found forC₂₈H₃₁N₇O₂ m/z 498.0 (M+H).

N-(6-(4-Methylpiperazin-1-yl)pyridin-3-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide70

Light yellow solid (37 mg, 0.07 mmol, 39.2% yield). ¹H NMR (DMSO-d₆) δppm 1.37-1.44 (m, 2H), 1.51 (quin, J=5 Hz, 4H), 2.22 (s, 3H), 2.35-2.42(m, 8H), 3.44 (t, J=5 Hz, 4H), 3.56 (s, 2H), 6.86 (d, J=9 Hz, 1H), 7.79(d, J=9 Hz, 1H), 7.82 (d, J=10 Hz, 1H), 7.98 (d, J=2 Hz, 1H), 8.03 (dd,J=9 Hz, J=3 Hz, 1H), 8.48 (d, J=11 Hz, 1H), 8.58 (d, 7=3 Hz, 1H), 8.81(d, J=3 Hz, 1H), 10.34 (s, 1H), 13.89 (brs, 1H); ESIMS found forC₂₉H₃₄N₈O m/z 511.5 (M+H).

5-(5-(Piperidin-1-ylmethyl)pyridin-3-yl)-N-(6-(pyrrolidin-1-yl)pyridin-3-yl)-1H-indazole-3-carboxamide 71

Tan solid (53.9 mg, 0.11 mmol, 53% yield). ¹H NMR (DMSO-d₆) δ ppm1.38-1.39 (m, 2H), 1.51-1.52 (m, 4H), 1.93-1.96 (m, 4H), 2.36-2.38 (m,4H), 3.36-3.39 (m, 4H), 3.56 (s, 2H), 6.46 (d, J=9 Hz, 1H), 7.78-7.83(m, 2H), 7.96 (dd, J=9 Hz, J=3 Hz, 1H), 7.98-7.99 (m, 1H), 8.46-8.47 (m,2H), 8.49 (, d, J=3 Hz, 1H), 8.80-8.81 (m, 1H), 10.23 (s, 1H), 13.87 (s,1H); ESIMS found for C₂₈H₃₁N₇O m/z 482 (M+H).

N-(6-(3-Fluorophenyl)pyridin-3-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide 72

White solid (54.8 mg, 0.11 mmol, 64% yield). ¹H NMR (DMSO-d₆) δ ppm1.39-1.40 (m, 2H), 1.50-1.54 (m, 4H), 2.38-2.39 (m, 4H), 3.57 (s, 2H),7.22-7.26 (m, 1H), 7.51-7.55 (m, 1H), 7.82-7.86 (m, 2H), 7.88-7.91 (m,1H), 7.94-7.96 (m, 1H), 8.00-8.01 (m, 1H), 8.06 (d, J=9 Hz, 1H), 8.46(dd, J=9 Hz, J=3 Hz, 1H), 8.50 (s, 2H), 8.82 (d, J=2 Hz, 1H), 9.20 (d,J=2 Hz, 1H), 10.86 (s, 1H), 14.03 (s, 1H); ESIMS found for C₃₀H₂₇FN₆Om/z 507 (M+H).

N-(6-(4-Fluorophenyl)pyridin-3-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide 73

White solid (50.8 mg, 0.10 mmol, 55% yield). ¹H NMR (DMSO-d₆) δ ppm1.39-1.40 (m, 2H), 1.49-1.53 (m, 4H), 2.36-2.39 (m, 4H), 3.57 (s, 2H),7.29-7.32 (m, 2H), 7.82-7.86 (m, 2H), 7.98-8.01 (m, 2H), 8.12-8.15 (m,2H), 8.43 (dd, J=9 Hz, J=3 Hz, 1H), 8.49 (s, 2H), 8.82 (d, J=2 Hz, 1H),9.17 (d, J=3 Hz, 1H), 10.81 (s, 1H), 14.02 (s, 1H); ESIMS found forC₃₀H₂₇FN₆O m/z 507 (M+H).

N-(6-((2-(Dimethylamino)ethyl)(methyl)amino)pyridin-3-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide74

Light yellow solid (88.5 mg, 0.17 mmol, 61.7% yield). NMR (DMSO-d₆) δppm 1.38-1.42 (m, 2H), 1.51 (quin, J=5 Hz, 4H), 2.18 (s, 6H), 2.34-2.40(m, 6H), 2.99 (s, 3H), 3.56 (s, 2H), 3.61 (t, J=7 Hz, 2H), 6.61 (d, J=9Hz, 1H), 7.79 (d, J=9 Hz, 1H), 7.81 (d, J=9 Hz, 1H), 7.95 (dd, J=9 Hz,J=3 Hz, 1H), 7.98 (t, J=2 Hz, 1H), 8.46 (s, 1H), 8.48 (d, J=2 Hz, 2H),8.81 (d, J=2 Hz, 1H), 10.24 (s, 1H), 13.84 (brs, 1H); ESIMS found forC₂₉H₃₆N₈O m/z 513.5 (M+H).

5-(5-(Piperidin-1-ylmethyl)pyridin-3-yl)-N-(pyridazin-4-yl)-1H-indazole-3-carboxamide75

White solid (53 mg, 0.13 mmol, 33.7% yield). ¹H NMR (DMSO-d₆) δ ppm1.36-1.43 (m, 2H), 1.47-1.54 (m, 4H), 2.33-2.42 (m, 4H), 3.57 (s, 2H),7.85 (s, 2H), 8.00 (t, J=2 Hz, 1H), 8.25 (dd, J=6 Hz, J=3 Hz, 1H), 8.47(t, J=1 Hz, 1H), 8.50 (d, J=2 Hz, 1H), 8.82 (d, J=2 Hz, 1H), 9.09 (d,J=6 Hz, 1H), 9.71 (dd, J=3 Hz, J=1 Hz, 1H), 11.16 (s, 1H), 14.16 (brs,1H); ESIMS found for C₂₃H₂₃N₇O m/z 414.1 (M+H).

5-(5-(Piperidin-1-ylmethyl)pyridin-3-yl)-N-(pyridin-3-ylmethyl)-1H-indazole-3-carboxamide76

White solid (26.8 mg, 0.06 mmol, 27% yield). ¹H NMR (DMSO-d₆) δ ppm1.38-1.39 (m, 2H), 1.49-1.51 (m, 4H), 2.36-2.37 (m, 4H), 3.55 (s, 2H),4.53 (d, J=6 Hz, 2H), 7.35 (dd, J=8 Hz, J=5 Hz, 1H), 7.74-7.80 (m, 3H),7.95-7.96 (m, 1H), 8.41-8.42 (m, 1H), 8.45-8.46 (m, 1H), 8.48-8.49 (m,1H), 8.58-8.59 (m, 1H), 8.78 (d, J=2 Hz, 1H), 9.17 (t, J=6 Hz, 1H),13.77 (s, 1H); ESIMS found for C₂₅H₂₆N₆O m/z 427 (M+H).

N-Cyclohexyl-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide77

White solid (50.4 mg, 0.12 mmol, 72.5% yield). ¹H NMR (DMSO-d₆) δ ppm1.12-1.47 (m, 7H), 1.50-1.53 (m, 4H), 1.60-1.63 (m, 1H), 1.73-1.75 (m,2H), 1.83-1.84 (m, 2H), 2.37-2.38 (m, 4H), 3.55 (s, 2H), 3.81-3.87 (m,1H), 7.73-7.78 (m, 2H), 7.95-7.96 (m, 1H), 8.14 (d, J=8 Hz, 1H),8.41-8.42 (m, 1H), 8.47 (d, J=2 Hz, 1H), 8.78 (d, J=2 Hz, 1H), 13.67 (s,1H); ESIMS found for C₂₅H₃₁N₃O m/z 418 (M+H).

N-(Benzo[d][1,3]dioxol-5-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide78

White solid (48.6 mg, 0.11 mmol, 22.1% yield). ¹H NMR (DMSO-d₆) δ ppm1.37-1.43 (m, 2H), 1.51 (quin, J=5 Hz, 4H), 2.36-2.42 (m, 4H), 3.56 (s,2H), 6.01 (s, 2H), 6.90 (d, J=9 Hz, 1H), 7.37 (dd, J=9 Hz, J=2 Hz, 1H),7.57 (d, J=2 Hz, 1H), 7.91 (dd, J=9 Hz, J=Hz, 1H), 7.82 (dd, J=9 Hz, 7=1Hz, 1H), 7.99 (t, J=2 Hz, 1H), 8.47 (dd, J=12 Hz, J=2 Hz, 1H), 8.81 (d,J=2 Hz, 1H), 10.34 (s, 1H), 13.89 (s, 1H); ESIMS found for C₂₆H₂₅N₅O₃m/z 456.0 (M+H).

N-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide 79

White solid (98.4 mg, 0.21 mmol, 38.7% yield). ¹H NMR (DMSO-d₆) δ ppm1.36-1.42 (m, 2H), 1.51 (quin, J=5 Hz, 4H), 2.34-2.41 (m, 4H), 3.56 (s,2H), 4.20-4.27 (m, 4H), 6.82 (d, J=9 Hz, 1H), 7.35 (dd, J=9 Hz, J=3 Hz,1H), 7.51 (d, J=3 Hz, 1H), 7.78 (dd, J=9 Hz, J=1 Hz, 1H), 7.81 (dd, J=9Hz, J=1 Hz, 1H), 7.98 (t, J=2 Hz, 1H), 8.47 (dd, J=12 Hz, J=2 Hz, 1H),8.81 (d, J=2 Hz, 1H), 10.26 (s, 1H), 13.87 (brs, 1H); ESIMS found forC₂₇H₂₇N₅O₃ m/z 470.4 (M+H).

N-(5-Benzylpyridin-3-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide80

White solid (81.9 mg, 0.16 mmol, 59% yield). ¹H NMR (DMSO-d₆) δ ppm1.39-1.41 (m, 2H), 1.49-1.53 (m, 4H), 2.37-2.39 (m, 4H), 3.56 (s, 2H),4.00 (s, 2H), 7.20-7.23 (m, 1H), 7.28-7.34 (m, 4H), 7.79-7.84 (m, 2H),7.98-7.99 (m, 1H), 8.23-8.24 (m, 1H), 8.25 (d, J=2 Hz, 1H), 8.45-8.46(m, 1H), 8.49 (d, J=2 Hz, 1H), 8.81 (d, J=2 Hz, 1H), 8.89 (d, J=2 Hz,1H), 10.65 (s, 1H), 13.97 (s, 1H); ESIMS found for C₃₁H₃₀N₆O m/z 503(M+H).

5-(5-(Piperidin-1-ylmethyl)pyridin-3-yl)-N-(pyrazin-2-yl)-1H-indazole-3-carboxamide81

White solid (104 mg, 0.25 mmol, 41.7% yield). ¹H NMR (DMSO-d₆) δ ppm1.35-1.42 (m, 2H), 1.51 (quin, J=5 Hz, 4H), 2.33-2.42 (m, 4H), 3.57 (s,2H), 7.83 (d, J=9 Hz, 1H), 7.85 (d, J=9 Hz, 1H), 8.00 (s, 1H), 8.45 (d,J=2 Hz, 1H), 8.46 (s, 1H), 8.50 (s, 1H), 8.83 (d, J=2 Hz, 1H), 9.50 (s,1H), 10.36 (s, 1H), 14.11 (brs, 1H); ESIMS found for C₂₃H₂₃N₇O m/z 413.9(M+H).

N-Phenyl-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide82

White solid (97.8 mg, 0.24 mmol, 81% yield). ¹H NMR (DMSO-d₆) δ ppm1.39-1.40 (m, 2H), 1.49-1.53 (m, 4H), 2.37-2.39 (m, 4H), 3.57 (s, 2H),7.09-7.12 (m, 1H), 7.34-7.37 (m, 2H), 7.80 (d, J=9 Hz, 1H), 7.83 (dd,J=9 Hz, 2 Hz, 1H), 7.907.92 (m, 2H), 7.99-8.00 (m, 1H), 8.47-8.48 (m,1H), 8.49 (d, J=2 Hz, 1H), 8.81 (d, J=2 Hz, 1H), 10.40 (s, 1H), 13.92(s, 1H); ESIMS found for C₂₅H₂₅N₅O m/z 412 (M+H).

(4-Methylpiperazin-1-yl)(5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazol-3-yl)methanone83

Light yellow amorphous solid (74.6 mg, 0.18 mmol, 93% yield). ¹H NMR(DMSO-d₆) δ ppm 1.38-1.39 (m, 2H), 1.48-1.53 (m, 4H), 2.22 (s, 3H),2.36-2.41 (m, 8H), 3.55 (s, 2H), 3.72-3.73 (m, 2H), 4.01-4.02 (m, 2H),7.73 (d, J=9 Hz, 1H), 7.79 (dd, J=9 Hz, J=2 Hz, 1H), 7.95-7.96 (m, 1H),8.22 (d, J=1 Hz, 1H), 8.46 (d, J=2 Hz, 1H), 8.78 (d, J=2 Hz, 1H), 13.64(s, 1H); ESIMS found for C₂₄H₃₀N₆O m/z 419 (M+H).

5-(5-(((2R,6S)-2,6-Dimethylpiperidin-1-yl)methyl)pyridin-3-yl)-N-(pyridin-3-yl)-1H-indazole-3-carboxamide84

Beige solid (76.5 mg, 0.17 mmol, 75.5% yield). ¹H NMR (DMSO-d₆) δ ppm1.00 (d, J=6 Hz, 6H), 1.21-1.35 (m, 3H), 1.55 (d, J=11 Hz, 2H),1.60-1.65 (m, 1H), 2.45-2.53 (m, 2H), 3.84 (s, 1H), 7.40 (dd, J=7 Hz, 3Hz, 1H), 7.79 (dd, J=9 Hz, J=2 Hz, 1H), 7.83 (dd, J=9 Hz, J=1 Hz, 1H),8.04 (s, 1H), 8.29-8.35 (m, 2H), 8.46 (s, 1H), 8.60 (d, J=2 Hz, 1H),8.73 (d, J=2 Hz, 1H), 9.08 (d, J=3 Hz, 1H), 10.70 (s, 1H), 14.00 (brs,1H); ESIMS found for C₂₆H₂₈N₆O m/z 441.3 (M+H).

N-(5-((Dimethylamino)methyl)pyridin-3-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide86

White solid (41.5 mg, 0.09 mmol, 72% yield). ¹H NMR (DMSO-d₆) δ ppm1.39-1.40 (m, 2H), 1.49-1.54 (m, 4H), 2.19 (s, 6H), 2.36-2.39 (m, 4H),3.44 (s, 2H), 3.58 (s, 2H), 7.81 (d, J=9 Hz, 1H), 7.85 (dd, J=9 Hz, J=2Hz, 1H), 8.00-8.01 (m, 1H), 8.21 (d, J=2 Hz, 1H), 8.37-8.38 (m, 1H),8.49-8.50 (m, 2H), 8.83 (d, J=2 Hz, 1H), 8.91 (d, J=2 Hz, 1H), 10.69 (s,1H), 14.01 (brs, 1H); ESIMS found for C₂₇H₃₁N₇O m/z 470 (M+H).

N-(1-Methylpiperidin-4-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide87

White amorphous solid (18.2 mg, 0.04 mmol, 59.8% yield). ¹H NMR(DMSO-d₆) δ ppm 1.39-1.40 (m, 2H), 1.49-1.53 (m, 4H), 1.66-1.75 (m, 4H),1.95-2.00 (m, 2H), 2.18 (s, 3H), 2.37-2.38 (m, 4H), 2.77 (d, J=11 Hz,2H), 3.55 (s, 2H), 3.81-3.83 (m, 1H), 7.73-7.75 (m, 1H), 7.77-7.79 (m,1H), 7.95-7.96 (m, 1H), 8.25 (d, J=8 Hz, 1H), 8.41-8.42 (m, 1H), 8.47(d, J=2 Hz, 1H), 8.78 (d, J=2 Hz, 1H), 13.70 (s, 1H); ESMS found forC₂₅H₃₂N₆O m/z 433 (M+H).

N-(5-((Dimethylamino)methyl)pyridin-3-yl)-5-(5-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide106

White solid (39.4 mg, 0.09 mmol, 74% yield). ¹H NMR (DMSO-d₆) δ ppm1.71-1.73 (m, 4H), 2.49-2.50 (m, 4H), 2.18 (s, 6H), 3.43 (s, 2H), 3.71(s, 2H), 7.81 (d, J=9 Hz, 1H), 7.84 (ABq, J=9 Hz, 1H), 8.02-8.03 (m,1H), 8.21 (d, J=2 Hz, 1H), 8.37-8.38 (m, 1H), 8.48-8.49 (m, 1H), 8.51(d, J=2 Hz, 1H), 8.83 (d, J=2 Hz, 1H), 8.91 (d, J=2 Hz, 1H), 10.68 (s,1H), 13.98 (s, 1H); ESIMS found for C₂₆H₂₉N₇O m/z 456 (M+H).

N-(5-((4-Methylpiperazin-1-yl)methyl)pyridin-3-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide124

N-(6-(Piperidin-1-yl)pyridin-3-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide126

Grey solid (92.7 mg, 0.19 mmol, 29.0% yield). ¹H NMR (DMSO-d₆) δ ppm1.48-1.64 (m, 12H), 2.32-2.43 (m, 4H), 3.48 (t, J=4.5 Hz, 4H), 3.56 (s,2H), 6.83 (d, J=9 Hz, 1H), 7.80 (ABq, J=10 Hz, 2H), 7.98 (s, 1H), 8.00(d, J=2.4 Hz, 1H), 8.47 (d, J=10 Hz, 2H), 8.55 (d, J=2.5 Hz, 1H), 8.81(d, J=2 Hz, 1H), 10.27 (s, 1H), 13.86 (s, 1H); ESIMS found for C₂₉H₃₃N₇Om/z 496.5 (M+H).

N-(3-Fluorophenyl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide162

White solid (176 mg, 0.41 mmol, 56.8% yield). ¹H NMR (DMSO-d₆) δ ppm1.36-1.43 (m, 2H), 1.47-1.55 (m, 4H), 2.38 (brs, 4H), 3.56 (s, 2H), 6.93(dt, J=9 Hz, J=3 Hz, 1H), 7.39 (q, J=8 Hz, 1H), 7.75 (dd, J=8 Hz, J=1Hz, 1H), 7.82 (d/Abq, J=9 Hz, J=1 Hz, 2H), 7.89 (td, J=12 Hz, J=2 Hz,1H), 7.99 (t, J=2 Hz, 1H), 8.47 (s, 1H), 8.49 (d, J=2 Hz, 1H), 8.82 (d,J=2 Hz, 1H), 10.66 (s, 1H), 13.97 (brs, 1H); ESIMS found for C₂₅H₂₄FN₅Om/z 430.0 (M+H).

5-(5-(Piperidin-1-ylmethyl)pyridin-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-indazole-3-carboxamide163

Tan amorphous solid (88 mg, 0.21 mmol, 88% yield). ¹H NMR (DMSO-d₆) δppm 1.39-1.40 (m, 2H), 1.49-1.53 (m, 4H), 1.69-1.76 (m, 4H), 2.37-2.38(m, 4H), 3.39-3.42 (m, 2H), 3.56 (s, 2H), 3.88-3.90 (m, 2H), 4.05-4.10(m, 1H), 7.74 (d, J=9 Hz, 1H), 7.77-7.79 (m, 1H), 7.95-7.96 (m, 1H),8.37 (d, J=8 Hz, 1H), 8.41-8.42 (m, 1H), 8.47 (d, J=2 Hz, 1H), 8.79 (d,J=2 Hz, 1H), 13.72 (s, 1H); ESMS found for C₂₄H₂₉N₅O₂ m/z 420 (M+H).

N-(5-Fluoropyridin-3-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide168

White solid (286 mg, 0.66 mmol, 56% yield). ¹H NMR (DMSO-d₆) δ ppm 1.39(m, 2H), 1.49-1.53 (m, 4H), 2.38 (brs, 4H), 3.56 (s, 2H), 7.81-7.86 (m,2H), 7.99 (s, 1H), 8.31-8.34 (m, 2H), 8.47 (s, 1H), 8.49 (d, J=1.3 Hz,1H), 8.82 (d, J=1.7 Hz, 1H), 8.99 (s, 1H), 10.97 (s, 1H), 14.07 (brs,1H); ESIMS found for C₂₄H₂₃FN₆O m/z 431.4 (M+H).

N-(6-(4-Hydroxypiperidin-1-yl)pyridin-3-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide169

Off-white solid (33 mg, 0.06 mmol, 53.8% yield). ¹H NMR (DMSO-d₆) δ ppm1.32-1.43 (m, 4H), 1.45-1.57 (m, 4H), 1.74-1.83 (m, 2H), 2.33-2.44 (m,4H), 3.04 (t, J=10 Hz, 2H), 3.56 (s, 2H), 3.63-3.73 (m, 1H), 3.93-4.02(m, 2H), 4.72 (s, 1H), 6.85 (d, 7=9 Hz, 1H), 7.80 (ABq, J=10 Hz, 2H),7.99 (d, J=7 Hz, 2H), 8.47 (d, J=10 Hz, 2H), 8.54 (s, 1H), 8.81 (s, 1H),10.28 (s, 1H), 13.87 (s, 1H); ESIMS found for C₂₉H₃₃N₇O₂ m/z 512.3(M+H).

5-(5-((4-Hydroxypiperidin-1-yl)methyl)pyridin-3-yl)-N-(6-(pyrrolidin-1-yl)pyridin-3-yl)-1H-indazole-3-carboxamide170

Off-white solid (125.4 mg, 0.25 mmol, 73.2% yield). ¹H NMR (DMSO-d₆) δppm 1.93-1.96 (m, 4H), 2.09-2.12 (m, 2H), 2.70-2.72 (m, 2H), 3.37-3.39(m, 4H), 3.46-3.47 (m, 1H), 3.58 (s, 1H), 4.52 (d, J=4 Hz, 1H), 6.46 d,J=9 Hz, 1H), 7.77-7.82 (m, 2H), 7.95-7.98 (m, 2H), 8.44-8.48 (m, 2H),8.49 (d, J=2.5 Hz, 1H), 8.80 (d, J=2.1 Hz, 1H), 10.20 (s, 1H), 13.85 (s,1H); ESIMS found for C₂₈H₃₁N₇O₂ m/z 498 (M+H).

N-(5-Methyl-6-(pyrrolidin-1-yl)pyridin-3-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide172

Off-white solid (186 mg, 0.38 mmol, 72.2% yield). ¹H NMR (DMSO-d₆) δ ppm1.34-1.43 (m, 2H), 1.47-1.55 (m, 4H), 1.82-1.89 (m, 4H), 2.30 s, 3H),2.33-2.42 (m, 4H), 3.43 (t, J=6.6 Hz, 4H), 3.56 (s, 2H), 7.81 (ABq, J=10Hz, 2H), 7.89 (d, J=2 Hz, 1H), 7.98 (s, 1H), 8.38 (d, J=2 Hz, 1H), 8.47(d, J=8 Hz, 2H), 8.81 (d, J=2 Hz, 1H), 10.24 (s, 1H), 13.86 (s, 1H);ESIMS found for C₂₉H₃₃N₇O m/z 496.4 (M+H).

N-(6-(Azetidin-1-yl)-5-methylpyridin-3-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide173

Off-white solid (184 mg, 0.38 mmol, 62.6% yield). ¹H NMR (DMSO-d₆) δ ppm1.35-1.43 (m, 2H), 1.47-1.54 (m, 4H), 2.16 (s, 3H), 2.22 (quin, J=7 Hz,2H), 2.34-2.42 (m, 4H), 3.56 (s, 2H), 4.00 (t, J=7 Hz, 4H), 7.81 (ABq,J=10 Hz, 2H), 7.85 (d, J=2 Hz, 1H), 8.39 (d, J=2 Hz, 1H), 8.47 (d, J=10Hz, 2H), 8.81 (d, J=2 Hz, 1H), 10.24 (s, 1H), 13.87 (s, 1H); ESIMS foundfor C₂₈H₃₁N₇O m/z 482.0 (M+H).

N-(6-(Azetidin-1-yl)pyridin-3-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide174

White solid (14.9 mg, 0.03 mmol, 11.0% yield). ¹H NMR (DMSO-d₆) δ ppm1.36-1.43 (m, 2H), 1.47-1.54 (m, 4H), 2.32 (quin, J=7 Hz, 2H), 2.35-2.42(m, 4H), 3.56 (s, 2H), 3.92 (t, J=7 Hz, 4H), 6.39 (d, J=9 Hz, 1H),7.77-7.83 (m, 2H), 7.98 (dd, J=9 Hz, J=2 Hz, 2H), 8.42-8.53 (m, 3H),8.78-8.84 (m, 1H), 10.27 (s, 1H), 13.87 (s, 1H), ESIMS found forC₂₇H₂₉N₇O m/z 468.0 (M+H).

N-(6-Methoxypyridin-3-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide175

White solid (31.2 mg, 0.07 mmol, 25.8% yield). ¹H NMR (DMSO-d₆) δ ppm1.36-1.43 (m, 2H), 1.47-1.55 (m, 4H), 2.33-2.42 (m, 4H), 3.56 (s, 2H),3.85 (s, 3H), 6.84 (d, J=9 Hz, 1H), 7.81 (ABq, J=12 Hz, 2H), 7.98 (s,1H), 8.18 (dd, J=9 Hz, J=2.7 Hz, 1H), 8.47 (dd, J=10 Hz, 7=1 Hz, 2H),8.65 (d, J=2.6 Hz, 1H), 8.81 (d, J=2 Hz, 1H), 10.50 (s, 1H), 13.91 (brs,1H); ESIMS found for C₂₅H₂₆N₆O₂ m/z 443.4 (M+H).

N-(2-Aminopyrimidin-5-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide176

Yellow solid (412 mg, 0.96 mmol, 52.5% yield). ¹H NMR (DMSO-d₆) δ ppm1.37-1.43 (m, 2H), 1.47-1.54 (m, 4H), 2.35-2.41 (m, 4H), 3.56 (s, 2H),6.49 (s, 2H), 7.81 (ABq, J=10 Hz, 2H), 7.98 (s, 1H), 8.47 (dd, J=12 Hz,J=2 Hz, 2H), 8.63 (s, 1H), 8.81 (d, J=2 Hz, 1H), 10.32 (s, 1H), 13.91(s, 1H); ESIMS found for C₂₃H₂₄N₈O m/z 429.3 (M+H).

N-(6-(Piperazin-1-yl)pyridin-3-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide177

Tan solid (160 mg, 0.32 mmol, 28.5% yield). ¹H NMR (DMSO-d₆) δ ppm1.37-1.43 (m, 2H), 1.48-1.54 (m, 4H), 2.34-2.41 (m, 4H), 2.79 (t, J=5Hz, 4H), 3.36 (t, J=5 Hz, 4H), 3.56 (s, 2H), 6.82 (d, J=9 Hz, 1H), 7.81(ABq, J=10 Hz, 2H), 7.98 (s, 1H), 8.02 (dd, J=9 Hz, J=2.7 Hz, 1H), 8.47(dd, J=9 Hz, J=2 Hz, 2H), 8.57 (d, J=2.5 Hz, 1H), 8.81 (d, J=2 Hz, 1H),10.29 (s, 1H); ESIMS found for C₂₈H₃₂N₈O m/z 497.1 (M+H).

N-(6-Hydroxypyridin-3-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide178

Off-white solid (78.3 mg, 0.18 mmol, 52.4% yield). ¹H NMR (DMSO-d₆) δppm 1.36-1.43 (m, 2H), 1.48-1.54 (m, 4H), 2.35-2.42 (m, 4H), 3.56 (s,2H), 6.38 (d, J=10 Hz, 1H), 7.80 (ABq, J=11 Hz, 2H), 7.83 (dd, J=10 Hz,J=3 Hz, 1H), 7.97 (s, 1H), 8.04 (d, J=2.5 Hz, 1H), 8.44 (s, 1H), 8.48(d, J=2 Hz, 1H), 8.80 (d, J=2 Hz, 1H), 10.27 (s, 1H), 11.42 (brs, 1H),13.87 (brs, 1H); ESIMS found for C₂₄H₂₄N₆O₂ m/z 429.1 (M+H).

5-(5-(Piperidin-1-ylmethyl)pyridin-3-yl)-N-(6-(pyrrolidine-1-carbonyl)pyridin-3-yl)-1H-indazole-3-carboxamide179

Light yellow solid (61 mg, 0.12 mmol, 37.8% yield). ¹H NMR (DMSO-d₆) δppm 1.37-1.43 (m, 2H), 1.48-1.55 (m, 4H), 1.82-1.90 (m, 4H), 2.38 (brs,4H), 3.17 (d, J=5 Hz, 2H), 3.51 (t, J=7 Hz, 2H), 3.57 (s, 2H), 3.70 (t,J=7 Hz, 2H), 7.79 (d, J=9 Hz, 1H), 7.84 (Abq, J=11 Hz, 2H), 8.00 (s,1H), 8.46 (dd, J=9 Hz, J=2.5 Hz, 1H), 8.48 (dd, J=9 Hz, J=2 Hz, 2H),8.82 (d, J=2 Hz, 1H), 9.10 (d, J=2 Hz, 1H), 10.91 (s, 1H), 14.05 (brs,1H); ESIMS found for C₂₉H₃₁N₇O₂ m/z 510.6 (M+H).

N-(6-(Cyclopentylcarbamoyl)pyridin-3-yl)-5-(pyridin-3-yl)-1H-indazole-3-carboxamide181

Light yellow solid (18 mg, 0.04 mmol, 16.6% yield). ¹H NMR (DMSO-d₆) δppm 1.50-1.64 (m, 4H), 1.67-1.76 (m, 2H), 1.85-1.94 (m, 4H), 4.24 (quin,J=8 Hz, 1H), 7.53 (dd, J=8 Hz, J=5 Hz, 1H), 7.84 (ABq, 2H), 8.03 (d, J=9Hz, 1H), 8.14 (d, J=8 Hz, 1H), 8.45 (d, J=8 Hz, 1H), 8.48 (s, 1H), 8.54(dd, J=9 Hz, J=2.5 Hz, 1H), 8.60 (d, J=4 Hz, 1H), 8.94 (d, J=2 Hz, 1H),9.16 (d, J=2 Hz, 1H), 10.97 (s, 1H), 14.08 (brs, 1H); ESIMS found forC₂₄H₂₂N₆O₂ m/z 427.1 (M+H).

5-(5-Aminopyridin-3-yl)-N-(6-(piperidin-1-yl)pyridin-3-yl)-1H-indazole-3-carboxamide182

Off-white solid (23.4 mg, 0.06 mmol, 19.4% yield). ¹H NMR (DMSO-d₆) δppm 1.51-1.63 (m, 6H), 3.47 (t, J=5 Hz, 4H), 5.45 (s, 2H), 6.83 (d, J=10Hz, 1H), 7.24 (t, J=2 Hz, 1H), 7.73 (dq, J=9 Hz, J=2 Hz, 2H), 7.94 (d,J=2.5 Hz, 1H), 8.00 (dd, J=9 Hz, J=2.5 Hz, 1H), 8.08 (d, J=2 Hz, 1H),8.40 (s, 1H), 8.56 (d, J=2.5 Hz, 1H), 10.27 (s, 1H), 13.84 (s, 1H);ESIMS found for C₂₃H₂₃N₇O m/z 414.3 (M+H).

5-(5-((3,3-Difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-N-(6-(pyrrolidin-1-yl)pyridin-3-yl)-1H-indazole-3-carboxamide183

Off-white solid (307 mg, 0.61 mmol, 39.6% yield). ¹H NMR (DMSO-d₆) δ ppm1.95 (t, J=6.5 Hz, 4H), 2.28 (tt, J=13.5 Hz, J=7 Hz, 2H), 2.76 (t, J=7Hz, 2H), 2.94 (t, J=13.5 Hz, 2H), 3.38 (t, J=6.5 Hz, 4H), 3.77 (s, 2H),6.46 (d, J=9 Hz, 1H), 7.81 (dq, J=8.5 Hz, J=1.5 Hz, 2H), 7.97 (dd, J=9Hz, J=2.5 Hz, 1H), 8.03 (s, 1H), 8.48 (s, 1H), 8.49 (d, J=2.5 Hz, 1H),8.52 (s, 1H), 8.84 (d, J=2 Hz, 1H), 10.23 (s, 1H), 13.87 (s, 1H); ESIMSfound for C₂₇H₂₇F₂N₇O m/z 504.0 (M+H).

N-(6-(Cyclopentylcarbamoyl)pyridin-3-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide184

White solid (3.2 mg, 0.01 mmol, 18.5% yield). ¹H NMR (DMSO-d₆) δ ppm1.36-1.43 (m, 2H), 1.43-1.64 (m, 8H), 1.64-1.76 (m, 2H), 1.82-1.93 (m,2H), 2.38 (brs, 4H), 3.57 (s, 2H), 4.24 (quin, J=7 Hz, 1H), 7.84 (ABq,J=10 Hz, 2H), 8.00 (s, 1H), 8.03 (d, J=9 Hz, 1H), 8.44 (d, J=8 Hz, 1H),8.48 (dd, J=8 Hz, J=2 Hz, 2H), 8.55 (dd, J=9 Hz, 7=2.5 Hz, 1H), 8.82 (d,J=2.5 Hz, 1H), 9.16 (d, J=2.5 Hz, 1H), 10.98 (s, 1H), 14.06 (brs, 1H);ESIMS found for C₃₀H₃₃N₇O₂ m/z 524.5 (M+H).

N-(6-(Methylsulfonyl)pyridin-3-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide 185

White solid (72 mg, 0.15 mmol, 56.4% yield). ¹H NMR (DMSO-d₆) δ ppm1.36-1.43 (m, 2H), 1.48-1.55 (m, 4H), 2.39 (brs, 4H), 3.27 (s, 3H), 3.57(s, 2H), 7.85 (s, 2H), 8.00 (s, 1H), 8.08 (d, J=8.5 Hz, 1H), 8.49 (dd,J=10 Hz, J=1.5 Hz, 2H), 8.83 (d, 7=2.5 Hz, 1H), 9.26 (d, J=2.5 Hz, 1H),11.19 (s, 1H), 14.13 (brs, 1H); ESIMS found for C₂₅H₂₆N₆O₃S m/z 491.1(M+H).

5-(5-(4-Methylpiperazin-1-yl)pyridin-3-yl)-N-(6-(pyrrolidin-1-yl)pyridin-3-yl)-1H-indazole-3-carboxamide186

Off-white solid (196 mg, 0.41 mmol, 47.8% yield). ¹H NMR (DMSO-d₆) δ ppm1.89-1.98 (m, 4H), 2.27 (brs, 3H), 3.25-3.42 (m, 12H), 6.45 (d, J=9 Hz,1H), 7.53 (s, 1H), 7.77 (q, J=8.5 Hz, 2H), 7.96 (d, J=6.5 Hz, 1H), 8.31(d, J=5.5 Hz, 2H), 8.43 (s, 1H), 8.48 (s, 1H), 10.21 (s, 1H), 13.83 (s,1H); ESIMS found for C₂₇H₃₀N₈O m/z 483.4 (M+H).

5-(5-Morpholinopyridin-3-yl)-N-(6-(pyrrolidin-1-yl)pyridin-3-yl)-1H-indazole-3-carboxamide187

White solid (92 mg, 0.20 mmol, 43.5% yield). ¹H NMR (DMSO-d₆) δ ppm 1.94(t, J=6.5 Hz, 4H), 3.28 (t, J=4.5 Hz, 4H), 3.38 (t, J=6.5 Hz, 4H), 3.78(t, J=4.5 Hz, 4H), 6.45 (d, J=9 Hz, 1H), 7.55 (s, 1H), 7.77 (dq, J=8.5Hz, J=1.5 Hz, 2H), 7.96 (dd, J=9 Hz, J=2.5 Hz 1H), 8.33 (dd, J=6.5 Hz,J=3 Hz, 2H), 8.44 (s, 1H), 8.49 (d, J=2.5 Hz, 1H), 10.21 (s, 1H), 13.83(s, 1H); ESIMS found for C₂₆H₂₇N₇O₂ m/z 470.5 (M+H).

5-(5-((3,3-Difluoropyrrolidin-1-yl)methyl)pyridin-3-yl)-N-(pyridin-3-yl)-1H-indazole-3-carboxamide188

White solid (209 mg, 0.48 mmol, 56.6% yield). ¹H NMR (DMSO-d₆) δ ppm2.23-2.32 (m, 2H), 2.76 (t, J=7 Hz, 2H), 2.94 (t, J=13.5 Hz, 2H), 3.77(s, 2H), 7.40 (q, J=8 Hz, 1H), 7.83 (dq, J=8 Hz, J=2 Hz, 2H), 8.04 (s,1H), 8.31-8.34 (m, 2H), 8.49 (s, 1H), 8.53 (d, J=2 Hz, 1H), 8.85 (d,J=2.5 Hz, 1H), 9.08 (d, J=2 Hz, 1H), 10.70 (s, 1H), 14.01 (brs, 1H);ESIMS found for C₂₃H₂₀F₂N₆O m/z 435.2 (M+H).

N-(Pyridin-3-yl)-5-(5-(pyrrolidin-1-yl)pyridin-3-yl)-1H-indazole-3-carboxamide189

White solid (30 mg, 0.08 mmol, 26.0% yield). ¹H NMR (DMSO-d₆) δ ppm1.91-2.05 (m, 4H), 3.33-3.39 (m, 4H), 7.09 (s, 1H), 7.40 (q, J=8 Hz,1H), 7.79 (s, 2H), 7.96 (d, J=2.5 Hz, 1H), 8.14 (s, 1H), 8.30-8.34 (m,2H), 8.44 (s, 1H), 9.07 (d, J=2 Hz, 1H), 10.68 (s, 1H), 13.97 (brs, 1H);ESIMS found for C₂₂H₂₀N₆O m/z 385.2 (M+H).

5-(5-((Dimethylamino)methyl)pyridin-3-yl)-N-(6-(pyrrolidin-1-yl)pyridin-3-yl)-1H-indazole-3-carboxamide190

White solid (142 mg, 0.32 mmol, 39.7% yield). ¹H NMR (DMSO-d₆) δ ppm1.92-1.97 (m, 4H), 2.20 (s, 6H), 3.35-3.40 (m, 4H), 3.53 (s, 2H), 6.46(d, J=9 Hz, 1H), 7.80 (dq, J=9 Hz, J=1.5 Hz, 2H), 7.97 (dd, J=9 Hz, J=3Hz, 1H), 8.00 (s, 1H), 8.46-8.50 (m, 3H), 8.82 (d, J=2.5 Hz, 1H), 10.22(s, 1H), 13.86 (brs, 1H); ESIMS found for C₂₅H₂₇N₇O m/z 442.4 (M+H).

Example 6

Preparation ofN-(6-(2-fluorophenoxy)pyridin-3-yl)-5-(pyridin-3-yl)-1H-indazole-3-carboxamide(18) is depicted below in Scheme 32.

Step 1

To a solution of methyl5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylate (CXVII)(7.0 g, 20.6 mmol) in DMF (80 mL) and water (16 mL) was added K₃PO₄(6.56 g, 30.9 mmol), pyridin-3-ylboronic acid (CXXXI) (2.79 g, 22.7mmol), Pd(PPh₃)₄ (1.19 g, 1.03 mmol) and. The solution was purged withargon and heated at 90° C. for 3 h. The solution was cooled to roomtemperature and then concentrated under reduced pressure. The residuewas dissolved in DCM and washed with water, dried over MgSO₄, filteredand then evaporated under vacuum. The residue was purified on a silicagel column (100% DCM→1.5:98.5 MeOH:DCM) to give methyl5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylate(CXXXIX) as an orange oil which solidified at rt (6.28 g, 18.6 mmol, 90%yield). ESIMS found for C₁₉H₁₉N₃O₃ m/z 338.0 (M+H).

Step 2

Preparation of intermediate5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylicacid (CXL) was performed following the procedure listed in Scheme 25,Step 4. White solid (900 mg, 2.78 mmol, 15% yield). ESIMS found forC₁₈H₁₇N₃O₃ m/z 324.1 (M+H).

Step 3

Preparation of intermediateN-(6-(2-fluorophenoxy)pyridin-3-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide(CXLI) was performed following the procedure listed in Scheme 28, Step3. Off-white solid (207 mg, 0.41 mmol, 66% yield). ¹H NMR (DMSO-d₆) δppm 1.60-1.69 (m, 2H), 1.76-1.87 (m, 1H), 2.03-2.13 (m, 2H), 2.56-2.65(m, 1H), 3.84 (dt, J=1 Hz, J=4 Hz, 1H), 3.99 (t, J=11 Hz, 1H), 6.07 (dd,J=10 Hz, J=2 Hz, 1H), 6.98 (dd, J=3 Hz, J=2 Hz, 1H), 7.03-7.08 (m, 2H),7.14 (d, J=9 Hz, 1H), 7.46 (t, J=7 Hz, 1H), 7.61 (dd, J=8 Hz, J=5 Hz,1H), 7.91 (dd, J=9 Hz, J=2 Hz, 1H), 8.05 (d, J=9 Hz, 1H), 8.25 (d, J=8Hz, 1H), 8.37 (dd, J=9 Hz, J=3 Hz, 1H), 8.49 (s, 1H), 8.64 (dd, J=5 Hz,J=2 Hz, 1H), 8.66 (d, J=3 Hz, 1H), 9.00 (d, J=2 Hz, 1H), 10.59 (s, 1H);ESIMS found for C₂₉H₂₄FN₅O₃ m/z 509.2 (M+H).

Step 4

Preparation ofN-(6-(2-fluorophenoxy)pyridin-3-yl)-5-(pyridin-3-yl)-1H-indazole-3-carboxamide(18) was performed following the procedure listed in Scheme 28, Step 4.White solid (128 mg, 0.30 mmol, 54.7% yield). ¹H NMR (DMSO-d₆) δ ppm7.16 (d, J=9 Hz, 1H), 7.23-7.39 (m, 4H), 7.52 (dd, J=8 Hz, J=5 Hz, 1H),7.79-7.85 (m, 2H), 8.13 (td, J=8 Hz, J=2 Hz, 1H), 8.38 (dd, J=9 Hz, J=3Hz, 1H), 8.46 (s, 1H), 8.56 (d, J=3 Hz, 1H), 8.59 (dd, J=5 Hz, 7=1 Hz,1H), 8.93 (d, J=2 Hz, 1H), 10.65 (s, 1H), 13.96 (brs, 1H); ESIMS foundfor C₂₄H₁₆FN₅O₂ m/z 426.0 (M+H).

The following compounds were prepared in accordance with the proceduredescribed in the above Example 6.

N-(6-(3-Fluorophenoxy)pyridin-3-yl)-5-(pyridin-3-yl)-1H-indazole-3-carboxamide19

Off-white solid (148 mg, 0.35 mmol, 89.3% yield). ¹H NMR (DMSO-d₆) δ ppm6.98 (dd, J=8 Hz, J=2 Hz, 1H), 7.01-7.06 (m, 2H), 7.13 (d, J=9 Hz, 1H),7.44 (q, J=7 Hz, 1H), 7.53 (dd, J=8 Hz, J=5 Hz, 1H), 7.80-7.85 (m, 2H),8.14 (td, J=6 Hz, J=2 Hz, 1H), 8.40 (dd, J=9 Hz, J=3 Hz, 1H), 8.47 (s,1H), 8.60 (dd, J=5 Hz, 7=1 Hz, 1H), 8.69 (d, J=3 Hz, 1H), 8.93 (d, J=2Hz, 1H), 10.71 (s, 1H), 13.99 (s, 1H); ESIMS found for C₂₄H₁₆FN₅O₂ m/z426.0 (M+H).

N-(6-(4-Fluorophenoxy)pyridin-3-yl)-5-(pyridin-3-yl)-1H-indazole-3-carboxamide20

White solid (82 mg, 0.19 mmol, 91.8% yield). ¹H NMR (DMSO-d₆) δ ppm 7.08(d, J=9 Hz, 1H), 7.15-7.21 (m, 2H), 7.22-7.27 (m, 2H), 7.67 (dd, J=8 Hz,J=5 Hz, 1H), 7.81-7.88 (m, 2H), 8.31 (d, J=8 Hz, 1H), 8.36 (dd, J=9 Hz,J=3 Hz, 1H), 8.51 (s, 1H), 8.63 (d, J=3 Hz, 1H), 8.66 (dd, J=5 Hz, 7=1Hz, 1H), 9.02 (d, 2 Hz, 1H), 10.67 (s, 1H), 14.00 (s, 1H); ESIMS foundfor C₂₄H₁₆FN₅O₂ m/z 426.0 (M+H).

Example 7

Preparation ofN-(6-carbamoylpyridin-3-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide(180) is depicted below in Scheme 33.

Step 1

To a solution ofN-(6-cyanopyridin-3-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide(62) (200 mg, 0.45 mmol) in glacial acetic acid (2 mL) heated at 85° C.was carefully added dropwise sulfuric acid (2 mL). The reaction washeated at 85° C. for another 20 minutes before pouring into ice. Thesolution was basified with cold 5N NH₄OH. The solids formed werefiltered, washed with cold washed and dried under vacuum. The dry solidwas suspended in DCM and a few drops of MeOH were added. The insolublesolids were filtered and discarded. The filtrate was concentrated andsuspended again in DCM, boiled for 15 minutes and filtered. The solidwas dried under vacuum to giveN-(6-carbamoylpyridin-3-yl)-5-(5-(piperidin-1-ylmethyl)pyridin-3-yl)-1H-indazole-3-carboxamide(180) as a white solid (192 mg, 0.42 mmol, 93.7% yield). ¹H NMR(DMSO-d₆) δ ppm 1.36-1.42 (m, 2H), 1.48-1.55 (m, 4H), 2.38 (brs, 4H),3.56 (s, 2H), 7.49 (s, 1H), 7.65 (d, J=9 Hz, 1H), 7.80 (d, J=9 Hz, 1H),7.97 (s, 1H), 8.03 (s, 2H), 8.41 (s, 1H), 8.45 (d, J=2 Hz, 1H), 8.54(dd, J=9 Hz, J=2.5 Hz, 1H), 8.80 (d, J=2 Hz, 1H), 9.15 (d, J=2 Hz, 1H),10.83 (brs, 1H); ESIMS found for C₂₅H₂₅N₇O₂ m/z 456.4 (M+H).

Administration and Pharmaceutical Compositions

Some embodiments include pharmaceutical compositions comprising: (a) asafe and therapeutically effective amount of the indazole-3-carboxamide,or its corresponding enantiomer, diastereoisomer or tautomer, orpharmaceutically acceptable salt; and (b) a pharmaceutically acceptablecarrier.

The compounds of this invention may also be useful in combination(administered together or sequentially) with other known agents.

Administration of the compounds disclosed herein or the pharmaceuticallyacceptable salts thereof can be via any of the accepted modes ofadministration for agents that serve similar utilities including, butnot limited to, orally, subcutaneously, intravenously, intranasally,topically, transdermally, intraperitoneally, intramuscularly,intrapulmonarilly, vaginally, rectally, ontologically,neuro-otologically, intraocularly, subconjuctivally, via anterior eyechamber injection, intravitreally, intraperitoneally, intrathecally,intracystically, intrapleurally, via wound irrigation, intrabuccally,intra-abdominally, intra-articularly, intra-aurally, intrabronchially,intracapsularly, intrameningeally, via inhalation, via endotracheal orendobronchial instillation, via direct instillation into pulmonarycavities, intraspinally, intrasynovially, intrathoracically, viathoracostomy irrigation, epidurally, intratympanically,intracisternally, intravascularly, intraventricularly, intraosseously,via irrigation of infected bone, or via application as part of anyadmixture with a prosthetic devices. Oral and parenteral administrationsare customary in treating the indications.

Compounds of the invention intended for pharmaceutical use may beadministered as crystalline or amorphous products. Pharmaceuticallyacceptable compositions may include solid, semi-solid, liquid,solutions, colloidal, liposomes, emulsions, suspensions, complexes,coacervates and aerosols. Dosage forms, such as, e.g., tablets,capsules, powders, liquids, suspensions, suppositories, aerosols,implants, controlled release or the like. They may be obtained, forexample, as solid plugs, powders, or films by methods such asprecipitation, crystallization, milling, grinding, supercritical fluidprocessing, coacervation, complex coacervation, encapsulation,emulsification, complexation, freeze drying, spray drying, orevaporative drying. Microwave or radio frequency drying may be used forthis purpose. The compounds can also be administered in sustained orcontrolled release dosage forms, including depot injections, osmoticpumps, pills (tablets and or capsules), transdermal (includingelectrotransport) patches, implants and the like, for prolonged and/ortimed, pulsed administration at a predetermined rate.

The compounds can be administered either alone or more typically incombination with a conventional pharmaceutical carrier, excipient or thelike. The term “excipient” is used herein to describe any ingredientother than the compound(s) of the invention. Pharmaceutically acceptableexcipients include, but are not limited to, ion exchangers, alumina,aluminum stearate, lecithin, self-emulsifying drug delivery systems(SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate,surfactants used in pharmaceutical dosage forms such as Tweens,poloxamers or other similar polymeric delivery matrices, serum proteins,such as human serum albumin, buffer substances such as phosphates, tris,glycine, sorbic acid, potassium sorbate, partial glyceride mixtures ofsaturated vegetable fatty acids, water, salts or electrolytes, such asprotamine sulfate, disodium hydrogen phosphate, potassium hydrogenphosphate, sodium-chloride, zinc salts, colloidal silica, magnesiumtrisilicate, polyvinyl pyrrolidone, cellulose-based substances,polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates,waxes, polyethylene-poly oxypropylene-block polymers, and wool fat.Cyclodextrins such as α-, β, and γ-cyclodextrin, or chemically modifiedderivatives such as hydroxyalkylcyclodextrins, including 2- and3-hydroxypropyl-b-cyclodextrins, or other solubilized derivatives canalso be advantageously used to enhance delivery of compounds of theformulae described herein. Dosage forms or compositions containing acompound as described herein in the range of 0.005% to 100% with thebalance made up from non-toxic carrier may be prepared. The contemplatedcompositions may contain 0.001%-100% active ingredient, in oneembodiment 0.1-95%, in another embodiment 75-85%, in a furtherembodiment 20-80%, Actual methods of preparing such dosage forms areknown, or will be apparent, to those skilled in this art; for example,see Remington: The Science and Practice of Pharmacy, 21st Edition(Lippincott Williams & Wilkins. 2005).

In one preferred embodiment, the compositions will take the form of aunit dosage form such as a pill or tablet and thus the composition maycontain, along with the active ingredient, a diluent such as lactose,sucrose, dicalcium phosphate, or the like; a lubricant such as magnesiumstearate or the like; and a binder such as starch, gum acacia,polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or thelike. In another solid dosage form, a powder, marume, solution orsuspension (e.g., in propylene carbonate, vegetable oils, PEG's,poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin orcellulose base capsule). Unit dosage forms in which the two activeingredients are physically separated are also contemplated; e.g.,capsules with granules (or tablets in a capsule) of each drug; two-layertablets; two-compartment gel caps, etc. Enteric coated or delayedrelease oral dosage forms are also contemplated.

Liquid pharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing, etc. an active compound as definedabove and optional pharmaceutical adjuvants in a carrier (e.g., water,saline, aqueous dextrose, glycerol, glycols, ethanol or the like) toform a solution, colloid, liposome, emulsion, complexes, coacervate orsuspension. If desired, the pharmaceutical composition can also containminor amounts of nontoxic auxiliary substances such as wetting agents,emulsifying agents, co-solvents, solubilizing agents, pH bufferingagents and the like (e.g., sodium acetate, sodium citrate, cyclodextrinederivatives, sorbitan monolaurate, triethanolamine acetate,triethanolamine oleate, and the like).

In some embodiments, the unit dosage of compounds of Formula (I) is 0.25mg/Kg to 50 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 0.25mg/Kg to 20 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 0.50mg/Kg to 19 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 0.75mg/Kg to 18 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 1.0mg/Kg to 17 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 1.25mg/Kg to 16 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 1.50mg/Kg to 15 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 1.75mg/Kg to 14 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 2.0mg/Kg to 13 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 3.0mg/Kg to 12 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 4.0mg/Kg to 11 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) is 5.0mg/Kg to 10 mg/Kg in humans.

In some embodiments, the compositions are provided in unit dosage formssuitable for single administration of a precise dose.

In some embodiments, the compositions are provided in unit dosage formssuitable for twice a day administration of a precise dose.

In some embodiments, the compositions are provided in unit dosage formssuitable for three times a day administration of a precise dose.

Injectables can be prepared in conventional forms, either as liquidsolutions, colloid, liposomes, complexes, coacervate or suspensions, asemulsions, or in solid forms suitable for reconstitution in liquid priorto injection. The percentage of active compound contained in suchparenteral compositions is highly dependent on the specific naturethereof, as well as the activity of the compound and the needs of thesubject. However, percentages of active ingredient of 0.01% to 10% insolution are employable, and could be higher if the composition is asolid or suspension, which could be subsequently diluted to the abovepercentages.

In some embodiments, the composition will comprise 0.1-10% of the activeagent in solution.

In some embodiments, the composition will comprise 0.1-5% of the activeagent in solution.

In some embodiments, the composition will comprise 0.1-4% of the activeagent in solution.

In some embodiments, the composition will comprise 0.15-3% of the activeagent in solution.

In some embodiments, the composition will comprise 0.2-2% of the activeagent in solution.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period of1-96 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period of1-72 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period of1-48 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period of1-24 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period of1-12 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period of1-6 hours.

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of 5 mg/m² to 300 mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of 5 mg/m² to 200 mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of 5 mg/m² to 100 mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of 10 mg/m² to 50 mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of 50 mg/m² to 200 mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of 75 mg/m² to 175 mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of 100 mg/m² to 150 mg/m².

In one preferred embodiment, the compositions can be administered to therespiratory tract (including nasal and pulmonary) e.g., through anebulizer, metered-dose inhalers, atomizer, mister, aerosol, dry powderinhaler, insufflator, liquid instillation or other suitable device ortechnique.

In some embodiments, aerosols intended for delivery to the nasal mucosaare provided for inhalation through the nose. For optimal delivery tothe nasal cavities, inhaled particle sizes of about 5 to about 100microns are useful, with particle sizes of about 10 to about 60 micronsbeing preferred. For nasal delivery, a larger inhaled particle size isdesired to maximize impaction on the nasal mucosa and to minimize orprevent pulmonary deposition of the administered formulation. In someembodiments, aerosols intended for delivery to the lung are provided forinhalation through the nose or the mouth. For optimal delivery to thelung, inhaled aerodynamic particle sizes of equal or less than 10 μm areuseful, with an aerodynamic particle size of about 0.1 to 10 micronsbeing preferred. Inhaled particles may be defined as liquid dropletscontaining dissolved drug, liquid droplets containing suspended drugparticles (in cases where the drug is insoluble in the suspendingmedium), dry particles of pure drug substance, drug substanceincorporated with excipients, liposomes, emulsions, colloidal systems,coacervates, aggregates of drug nanoparticles, or dry particles of adiluent which contain embedded drug nanoparticles.

In some embodiments, compounds of Formula (I) disclosed herein intendedfor respiratory delivery (either systemic or local) can be administeredas aqueous formulations, as non-aqueous solutions or suspensions, assuspensions or solutions in halogenated hydrocarbon propellants with orwithout alcohol, as a colloidal system, as emulsions, coacervates or asdry powders. Aqueous formulations may be aerosolized by liquidnebulizers employing either hydraulic or ultrasonic atomization or bymodified micropump systems (like the soft mist inhalers, the Aerodose®or the AERx® systems). Propellant-based systems may use suitablepressurized metered-dose inhalers (pMDIs). Dry powders may use drypowder inhaler devices (DPIs), which are capable of dispersing the drugsubstance effectively. A desired particle size and distribution may beobtained by choosing an appropriate device.

In some embodiments, the compositions of Formula (I) disclosed hereincan be administered to the ear by various methods. For example, a roundwindow catheter (e.g., U.S. Pat. Nos. 6,440,102 and 6,648,873) can beused.

Alternatively, formulations can be incorporated into a wick for usebetween the outer and middle ear (e.g., U.S. Pat. No. 6,120,484) orabsorbed to collagen sponge or other solid support (e.g., U.S. Pat. No.4,164,559).

If desired, formulations of the invention can be incorporated into a gelformulation (e.g., U.S. Pat. Nos. 4,474,752 and 6,911,211).

In some embodiments, compounds of Formula (I) disclosed herein intendedfor delivery to the ear can be administered via an implanted pump anddelivery system through a needle directly into the middle or inner ear(cochlea) or through a cochlear implant stylet electrode channel oralternative prepared drug delivery channel such as but not limited to aneedle through temporal bone into the cochlea.

Other options include delivery via a pump through a thin film coatedonto a multichannel electrode or electrode with a specially imbeddeddrug delivery channel (pathways) carved into the thin film for thispurpose. In other embodiments the acidic or basic solid gacyclidine canbe delivered from the reservoir of an external or internal implantedpumping system.

Formulations of the invention also can be administered to the ear byintratympanic injection into the middle ear, inner ear, or cochlea(e.g., U.S. Pat. No. 6,377,849 and Ser. No. 11/337,815).

Intratympanic injection of therapeutic agents is the technique ofinjecting a therapeutic agent behind the tympanic membrane into themiddle and/or inner ear. In one embodiment, the formulations describedherein are administered directly onto the round window membrane viatranstympanic injection. In another embodiment, the ion channelmodulating agent auris-acceptable formulations described herein areadministered onto the round window membrane via a non-transtympanicapproach to the inner ear. In additional embodiments, the formulationdescribed herein is administered onto the round window membrane via asurgical approach to the round window membrane comprising modificationof the crista fenestrae cochleae.

In some embodiments, the compounds of Formula (I) are formulated inrectal compositions such as enemas, rectal gels, rectal foams, rectalaerosols, suppositories, jelly suppositories, or retention enemas,containing conventional suppository bases such as cocoa butter or otherglycerides, as well as synthetic polymers such as polyvinylpyrrolidone,PEG (like PEG ointments), and the like. In suppository forms of thecompositions, a low-melting wax such as, but not limited to, a mixtureof fatty acid glycerides, optionally in combination with cocoa butter isfirst melted.

Suppositories for rectal administration of the drug (either as asolution, colloid, suspension or a complex) can be prepared by mixingthe drug with a suitable non-irritating excipient that is solid atordinary temperatures but liquid at the rectal temperature and willtherefore melt or erode/dissolve in the rectum and release the drug.Such materials include cocoa butter, glycerinated gelatin, hydrogenatedvegetable oils, poloxamers, mixtures of polyethylene glycols of variousmolecular weights and fatty acid esters of polyethylene glycol.

It is to be noted that concentrations and dosage values may also varywith the severity of the condition to be alleviated. It is to be furtherunderstood that for any particular patient, specific dosage regimensshould be adjusted over time according to the individual need and theprofessional judgment of the person administering or supervising theadministration of the compositions, and that the concentration rangesset forth herein are exemplary only and are not intended to limit thescope or practice of the claimed compositions.

Solid compositions can be provided in various different types of dosageforms, depending on the physicochemical properties of the drug, thedesired dissolution rate, cost considerations, and other criteria. Inone of the embodiments, the solid composition is a single unit. Thisimplies that one unit dose of the drug is comprised in a single,physically shaped solid form or article. In other words, the solidcomposition is coherent, which is in contrast to a multiple unit dosageform, in which the units are incoherent.

Examples of single units which may be used as dosage forms for the solidcomposition include tablets, such as compressed tablets, film-likeunits, foil-like units, wafers, lyophilized matrix units, and the like.In a preferred embodiment, the solid composition is a highly porouslyophilized form. Such lyophilizates, sometimes also called wafers orlyophilized tablets, are particularly useful for their rapiddisintegration, which also enables the rapid dissolution of the activecompound.

On the other hand, for some applications the solid composition may alsobe formed as a multiple unit dosage form as defined above. Examples ofmultiple units are powders, granules, microparticles, pellets,mini-tablets, beads, lyophilized powders, and the like. In oneembodiment, the solid composition is a lyophilized powder. Such adispersed lyophilized system comprises a multitude of powder particles,and due to the lyophilization process used in the formation of thepowder, each particle has an irregular, porous microstructure throughwhich the powder is capable of absorbing water very rapidly, resultingin quick dissolution. Effervescent compositions are also contemplated toaid the quick dispersion and absorption of the compound.

Another type of multiparticulate system which is also capable ofachieving rapid drug dissolution is that of powders, granules, orpellets from water-soluble excipients which are coated with the drug, sothat the drug is located at the outer surface of the individualparticles. In this type of system, the water-soluble low molecularweight excipient is useful for preparing the cores of such coatedparticles, which can be subsequently coated with a coating compositioncomprising the drug and, preferably, one or more additional excipients,such as a binder, a pore former, a saccharide, a sugar alcohol, afilm-forming polymer, a plasticizer, or other excipients used inpharmaceutical coating compositions.

Also provided herein are kits. Typically, a kit includes one or morecompounds or compositions as described herein. In certain embodiments, akit can include one or more delivery systems, e.g., for delivering oradministering a compound as provided above, and directions for use ofthe kit (e.g., instructions for treating a patient). In anotherembodiment, the kit can include a compound or composition as describedherein and a label that indicates that the contents are to beadministered to a patient with cancer. In another embodiment, the kitcan include a compound or composition as described herein and a labelthat indicates that the contents are to be administered to a patientwith one or more of hepatocellular carcinoma, colon cancer, leukemia,lymphoma, sarcoma, ovarian cancer, diabetic retinopathy, pulmonaryfibrosis, rheumatoid arthritis, scleroderma, mycotic and viralinfections, bone and cartilage diseases, Alzheimer's disease, lungdisease, osteoarthritis, polyposis coli, bone density and vasculardefects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familialexudative vitreoretinopathy, retinal angiogenesis, early coronarydisease, tetra-amelia, Müllerian-duct regression and virilization,SERKAL syndrome, type II diabetes, Fuhrmann syndrome,Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia,focal dermal hypoplasia, autosomal recessive anonychia, neural tubedefects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICFsyndrome, Angelman's syndrome, Prader-Willi syndrome, Beckwith-WiedemannSyndrome, Norrie disease and Rett syndrome

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

Methods of Treatment

The compounds and compositions provided herein can be used as inhibitorsand/or modulators of one or more components of the Wnt pathway, whichmay include one or more Wnt proteins, and thus can be used to treat avariety of disorders and diseases in which aberrant Wnt signaling isimplicated, such as cancer and other diseases associated with abnormalangiogenesis, cellular proliferation, and cell cycling. Accordingly, thecompounds and compositions provided herein can be used to treat cancer,to reduce or inhibit angiogenesis, to reduce or inhibit cellularproliferation, to correct a genetic disorder, and/or to treat aneurological condition/disorder/disease due to mutations ordysregulation of the Wnt pathway and/or of one or more of Wnt signalingcomponents. Non-limiting examples of diseases which can be treated withthe compounds and compositions provided herein include a variety ofcancers, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis,scleroderma, mycotic and viral infections, bone and cartilage diseases,neurological conditions/diseases such as Alzheimer's disease,amyotrophic lateral sclerosis (ALS), motor neurone disease, multiplesclerosis or autism, lung disease, osteoarthritis, polyposis coli, bonedensity and vascular defects in the eye (Osteoporosis-pseudogliomaSyndrome, OPPG), familial exudative vitreoretinopathy, retinalangiogenesis, early coronary disease, tetra-amelia, Müllerian-ductregression and virilization, SERKAL syndrome, type II diabetes, Fuhrmannsyndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia,focal dermal hypoplasia, autosomal recessive anonychia, neural tubedefects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICFsyndrome, Angelman's syndrome, Prader-Willi syndrome, Beckwith-WiedemannSyndrome, Norrie disease and Rett syndrome.

With respect to cancer, the Wnt pathway is known to be constitutivelyactivated in a variety of cancers including, for example, colon cancer,hepatocellular carcinoma, lung cancer, ovarian cancer, prostate cancer,pancreatic cancer and leukemias such as CML, CLL and T-ALL. Theconstitutive activation is due to constitutively active β-catenin,perhaps due to its stabilization by interacting factors or inhibition ofthe degradation pathway. Accordingly, the compounds and compositionsdescribed herein may be used to treat these cancers in which the Wntpathway is constitutively activated. In certain embodiments, the canceris chosen from hepatocellular carcinoma, colon cancer, leukemia,lymphoma, sarcoma and ovarian cancer.

Other cancers can also be treated with the compounds and compositionsdescribed herein.

More particularly, cancers that may be treated by the compound,compositions and methods described herein include, but are not limitedto, the following:

1) Breast cancers, including, for example ER⁺ breast cancer, ER⁻ breastcancer, her2⁻ breast cancer, her2⁺ breast cancer, stromal tumors such asfibroadenomas, phyllodes tumors, and sarcomas, and epithelial tumorssuch as large duct papillomas; carcinomas of the breast including insitu (noninvasive) carcinoma that includes ductal carcinoma in situ(including Paget's disease) and lobular carcinoma in situ, and invasive(infiltrating) carcinoma including, but not limited to, invasive ductalcarcinoma, invasive lobular carcinoma, medullary carcinoma, colloid(mucinous) carcinoma, tubular carcinoma, and invasive papillarycarcinoma; and miscellaneous malignant neoplasms. Further examples ofbreast cancers can include luminal A, luminal B, basal A, basal B, andtriple negative breast cancer, which is estrogen receptor negative(ER⁻), progesterone receptor negative, and her2 negative (her2⁻). Insome embodiments, the breast cancer may have a high risk Oncotype score.

2) Cardiac cancers, including, for example sarcoma, e.g., angiosarcoma,fibrosarcoma, rhabdomyosarcoma, and liposarcoma; myxoma; rhabdomyoma;fibroma; lipoma and teratoma.

3) Lung cancers, including, for example, bronchogenic carcinoma, e.g.,squamous cell, undifferentiated small cell, undifferentiated large cell,and adenocarcinoma; alveolar and bronchiolar carcinoma; bronchialadenoma; sarcoma; lymphoma; chondromatous hamartoma; and mesothelioma.

4) Gastrointestinal cancer, including, for example, cancers of theesophagus, e.g., squamous cell carcinoma, adenocarcinoma,leiomyosarcoma, and lymphoma; cancers of the stomach, e.g., carcinoma,lymphoma, and leiomyosarcoma; cancers of the pancreas, e.g., ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,and vipoma; cancers of the small bowel, e.g., adenocarcinoma, lymphoma,carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma,neurofibroma, and fibroma; cancers of the large bowel, e.g.,adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, andleiomyoma.

) Genitourinary tract cancers, including, for example, cancers of thekidney, e.g., adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma,and leukemia; cancers of the bladder and urethra, e.g., squamous cellcarcinoma, transitional cell carcinoma, and adenocarcinoma; cancers ofthe prostate, e.g., adenocarcinoma, and sarcoma; cancer of the testis,e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, and lipoma.

6) Liver cancers, including, for example, hepatoma, e.g., hepatocellularcarcinoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma;hepatocellular adenoma; and hemangioma.

7) Bone cancers, including, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochrondroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma and giant celltumors.

8) Nervous system cancers, including, for example, cancers of the skull,e.g., osteoma, hemangioma, granuloma, xanthoma, and osteitis deformans;cancers of the meninges, e.g., meningioma, meningiosarcoma, andgliomatosis; cancers of the brain, e.g., astrocytoma, medulloblastoma,glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, and congenital tumors;and cancers of the spinal cord, e.g., neurofibroma, meningioma, glioma,and sarcoma.

9) Gynecological cancers, including, for example, cancers of the uterus,e.g., endometrial carcinoma; cancers of the cervix, e.g., cervicalcarcinoma, and pre tumor cervical dysplasia; cancers of the ovaries,e.g., ovarian carcinoma, including serous cystadenocarcinoma, mucinouscystadenocarcinoma, unclassified carcinoma, granulosa theca cell tumors,Sertoli Leydig cell tumors, dysgerminoma, and malignant teratoma;cancers of the vulva, e.g., squamous cell carcinoma, intraepithelialcarcinoma, adenocarcinoma, fibrosarcoma, and melanoma; cancers of thevagina, e.g., clear cell carcinoma, squamous cell carcinoma, botryoidsarcoma, and embryonal rhabdomyosarcoma; and cancers of the fallopiantubes, e.g., carcinoma.

10) Hematologic cancers, including, for example, cancers of the blood,e.g., acute myeloid leukemia, chronic myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferativediseases, multiple myeloma, and myelodysplastic syndrome, Hodgkin'slymphoma, non Hodgkin's lymphoma (malignant lymphoma) and Waldenström'smacroglobulinemia.

11) Skin cancers and skin disorders, including, for example, malignantmelanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi'ssarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma,keloids, and scleroderma.

12) Adrenal gland cancers, including, for example, neuroblastoma.

Cancers may be solid tumors that may or may not be metastatic. Cancersmay also occur, as in leukemia, as a diffuse tissue. Thus, the term“tumor cell,” as provided herein, includes a cell afflicted by any oneof the above identified disorders.

A method of treating cancer using a compound or composition as describedherein may be combined with existing methods of treating cancers, forexample by chemotherapy, irradiation, or surgery (e.g., oophorectomy).In some embodiments, a compound or composition can be administeredbefore, during, or after another anticancer agent or treatment.

The compounds and compositions described herein can be used asanti-angiogenesis agents and as agents for modulating and/or inhibitingthe activity of protein kinases, thus providing treatments for cancerand other diseases associated with cellular proliferation mediated byprotein kinases. Accordingly, provided herein is a method of treatingcancer or preventing or reducing angiogenesis through kinase inhibition.

In addition, and including treatment of cancer, the compounds andcompositions described herein can function as cell-cycle control agentsfor treating proliferative disorders in a patient. Disorders associatedwith excessive proliferation include, for example, cancers, scleroderma,immunological disorders involving undesired proliferation of leukocytes,and restenosis and other smooth muscle disorders. Furthermore, suchcompounds may be used to prevent de-differentiation of post-mitotictissue and/or cells.

Diseases or disorders associated with uncontrolled or abnormal cellularproliferation include, but are not limited to, the following:

-   -   a variety of cancers, including, but not limited to, carcinoma,        hematopoietic tumors of lymphoid lineage, hematopoietic tumors        of myeloid lineage, tumors of mesenchymal origin, tumors of the        central and peripheral nervous system and other tumors including        melanoma, seminoma and Kaposi's sarcoma.    -   a disease process which features abnormal cellular        proliferation, e.g., benign prostatic hyperplasia, familial        adenomatosis polyposis, neurofibromatosis, atherosclerosis,        arthritis, glomerulonephritis, restenosis following angioplasty        or vascular surgery, inflammatory bowel disease, transplantation        rejection, endotoxic shock, and fungal infections. Fibrotic        disorders such as skin fibrosis; scleroderma; progressive        systemic fibrosis; lung fibrosis; muscle fibrosis; kidney        fibrosis; glomerulosclerosis; glomerulonephritis; hypertrophic        scar formation; uterine fibrosis; renal fibrosis; cirrhosis of        the liver, liver fibrosis; adhesions, such as those occurring in        the abdomen, pelvis, spine or tendons; chronic obstructive        pulmonary disease; fibrosis following myocardial infarction;        pulmonary fibrosis; fibrosis and scarring associated with        diffuse/interstitial lung disease; central nervous system        fibrosis, such as fibrosis following stroke; fibrosis associated        with neurodegenerative disorders such as Alzheimer's Disease or        multiple sclerosis; fibrosis associated with proliferative        vitreoretinopathy (PVR); restenosis; endometriosis; ischemic        disease and radiation fibrosis.    -   defective apoptosis-associated conditions, such as cancers        (including but not limited to those types mentioned herein),        viral infections (including but not limited to herpesvirus,        poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus),        prevention of AIDS development in HIV-infected individuals,        autoimmune diseases (including but not limited to systemic lupus        erythematosus, rheumatoid arthritis, scleroderma, autoimmune        mediated glomerulonephritis, inflammatory bowel disease and        autoimmune diabetes mellitus), neurodegenerative disorders        (including but not limited to Alzheimer's disease, lung disease,        amyotrophic lateral sclerosis, retinitis pigmentosa, Parkinson's        disease, AIDS-related dementia, spinal muscular atrophy and        cerebellar degeneration), myelodysplastic syndromes, aplastic        anemia, ischemic injury associated with myocardial infarctions,        stroke and reperfusion injury, arrhythmia, atherosclerosis,        toxin-induced or alcohol related liver diseases, hematological        diseases (including but not limited to chronic anemia and        aplastic anemia), degenerative diseases of the musculoskeletal        system (including but not limited to osteoporosis and        arthritis), aspirin-sensitive rhinosinusitis, cystic fibrosis,        multiple sclerosis, kidney diseases and cancer pain.    -   genetic diseases due to mutations in Wnt signaling components,        such as polyposis coli, bone density and vascular defects in the        eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial        exudative vitreoretinopathy, retinal angiogenesis, early        coronary disease, tetra-amelia, Müllerian-duct regression and        virilization, SERKAL syndrome, type II diabetes, Fuhrmann        syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,        odonto-onycho-dermal dysplasia, obesity, split-hand/foot        malformation, caudal duplication, tooth agenesis, Wilms tumor,        skeletal dysplasia, focal dermal hypoplasia, autosomal recessive        anonychia, neural tube defects, alpha-thalassemia (ATRX)        syndrome, fragile X syndrome, ICF syndrome, Angelman's syndrome,        Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie        disease and Rett syndrome.

Furthermore, the compounds and compositions described herein can be usedto treat neurological conditions, disorders and/or diseases caused bydysfunction in the Wnt signaling pathway. Non-limiting examples ofneurological conditions/disorders/diseases which can be treated with thecompounds and compositions provided herein include Alzheimer's disease,aphasia, apraxia, arachnoiditis, ataxia telangiectasia, attentiondeficit hyperactivity disorder, auditory processing disorder, autism,alcoholism, Bell's palsy, bipolar disorder, brachial plexus injury,Canavan disease, carpal tunnel syndrome, causalgia, central painsyndrome, central pontine myelinolysis, centronuclear myopathy, cephalicdisorder, cerebral aneurysm, cerebral arteriosclerosis, cerebralatrophy, cerebral gigantism, cerebral palsy, cerebral vasculitis,cervical spinal stenosis, Charcot-Marie-Tooth disease, Chiarimalformation, chronic fatigue syndrome, chronic inflammatorydemyelinating polyneuropathy (CIDP), chronic pain, Coffin-Lowrysyndrome, complex regional pain syndrome, compression neuropathy,congenital facial diplegia, corticobasal degeneration, cranialarteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulativetrauma disorder, Cushing's syndrome, cytomegalic inclusion body disease(CIBD), Dandy-Walker syndrome, Dawson disease, De Morsier's syndrome,Dejerine-Klumpke palsy, Dejerine-Sottas disease, delayed sleep phasesyndrome, dementia, dermatomyositis, developmental dyspraxia, diabeticneuropathy, diffuse sclerosis, Dravet syndrome, dysautonomia,dyscalculia, dysgraphia, dyslexia, dystonia, empty sella syndrome,encephalitis, encephalocele, encephalotrigeminal angiomatosis,encopresis, epilepsy, Erb's palsy, erythromelalgia, essential tremor,Fabry's disease, Fahr's syndrome, familial spastic paralysis, febrileseizure, Fisher syndrome, Friedreich's ataxia, fibromyalgia, Foville'ssyndrome, Gaucher's disease, Gerstmann's syndrome, giant cell arteritis,giant cell inclusion disease, globoid cell leukodystrophy, gray matterheterotopia, Guillain-Barré syndrome, HTLV-1 associated myelopathy,Hallervorden-Spatz disease, hemifacial spasm, hereditary spasticparaplegia, heredopathia atactica polyneuritiformis, herpes zosteroticus, herpes zoster, Hirayama syndrome, holoprosencephaly,Huntington's disease, hydranencephaly, hydrocephalus, hypercortisolism,hypoxia, immune-mediated encephalomyelitis, inclusion body myositis,incontinentia pigmenti, infantile phytanic acid storage disease,infantile Refsum disease, infantile spasms, inflammatory myopathy,intracranial cyst, intracranial hypertension, Joubert syndrome, Karaksyndrome, Kearns-Sayre syndrome, Kennedy disease, Kinsboume syndrome,Klippel Feil syndrome, Krabbe disease, Kugelberg-Welander disease, kuru,Lafora disease, Lambert-Eaton myasthenic syndrome, Landau-Kleffnersyndrome, lateral medullary (Wallenberg) syndrome, Leigh's disease,Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, leukodystrophy, Lewy bodydementia, lissencephaly, locked-in syndrome, Lou Gehrig's disease,lumbar disc disease, lumbar spinal stenosis, Lyme disease,Machado-Joseph disease (Spinocerebellar ataxia type 3), macrencephaly,macropsia, megalencephaly, Melkersson-Rosenthal syndrome, Menieresdisease, meningitis, Menkes disease, etachromatic leukodystrophy,microcephaly, micropsia, Miller Fisher syndrome, misophonia,mitochondrial myopathy, Mobius syndrome, monomelic amyotrophy, motorneurone disease, motor skills disorder, Moyamoya disease,mucopolysaccharidoses, multi-infarct dementia, multifocal motorneuropathy, multiple sclerosis, multiple system atrophy, musculardystrophy, myalgic encephalomyelitis, myasthenia gravis, myelinoclasticdiffuse sclerosis, myoclonic Encephalopathy of infants, myoclonus,myopathy, myotubular myopathy, myotonia congenital, narcolepsy,neurofibromatosis, neuroleptic malignant syndrome, lupus erythematosus,neuromyotonia, neuronal ceroid lipofuscinosis, Niemann-Pick disease,O'Sullivan-McLeod syndrome, occipital Neuralgia, occult SpinalDysraphism Sequence, Ohtahara syndrome, olivopontocerebellar atrophy,opsoclonus myoclonus syndrome, optic neuritis, orthostatic hypotension,palinopsia, paresthesia, Parkinson's disease, paramyotonia Congenita,paraneoplastic diseases, paroxysmal attacks, Parry-Romberg syndrome,Pelizaeus-Merzbacher disease, periodic paralyses, peripheral neuropathy,photic sneeze reflex, phytanic acid storage disease, Pick's disease,polymicrogyria (PMG), polymyositis, porencephaly, post-polio syndrome,postherpetic neuralgia (PHN), postural hypotension, Prader-Willisyndrome, primary lateral sclerosis, prion diseases, progressivehemifacial atrophy, progressive multifocal leukoencephalopathy,progressive supranuclear palsy, pseudotumor cerebri, Ramsay Huntsyndrome type I, Ramsay Hunt syndrome type II, Ramsay Hunt syndrome typeIII, Rasmussen's encephalitis, reflex neurovascular dystrophy, Refsumdisease, restless legs syndrome, retrovirus-associated myelopathy, Rettsyndrome, Reye's syndrome, rhythmic movement disorder, Romberg syndrome,Saint Vitus dance, Sandhoff disease, schizophrenia, Schilder's disease,schizencephaly, sensory integration dysfunction, septo-optic dysplasia,Shy-Drager syndrome, Sjögren's syndrome, snatiation, Sotos syndrome,spasticity, spina bifida, spinal cord tumors, spinal muscular atrophy,spinocerebellar ataxia, Steele-Richardson-Olszewski syndrome,Stiff-person syndrome, stroke, Sturge-Weber syndrome, subacutesclerosing panencephalitis, subcortical arteriosclerotic encephalopathy,superficial siderosis, Sydenham's chorea, syncope, synesthesia,syringomyelia, tarsal tunnel syndrome, tardive dyskinesia, tardivedysphrenia, Tarlov cyst, Tay-Sachs disease, temporal arteritis, tetanus,tethered spinal cord syndrome, Thomsen disease, thoracic outletsyndrome, tic douloureux, Todd's paralysis, Tourette syndrome, toxicencephalopathy, transient ischemic attack, transmissible spongiformencephalopathies, transverse myelitis, tremor, trigeminal neuralgia,tropical spastic paraparesis, trypanosomiasis, tuberous sclerosis,ubisiosis, Von Hippel-Lindau disease (VHL), Viliuisk Encephalomyelitis(VE), Wallenberg's syndrome, Werdnig, Hoffman disease, west syndrome,Williams syndrome, Wilson's disease and Zellweger syndrome.

The compounds and compositions may also be useful in the inhibition ofthe development of invasive cancer, tumor angiogenesis and metastasis.

In some embodiment, the invention provides a method for treating adisease or disorder associated with aberrant cellular proliferation byadministering to a patient in need of such treatment an effective amountof one or more of the compounds of Formula (I), in combination(simultaneously or sequentially) with at least one other agent.

In some embodiments, the pharmaceutical composition comprises atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.

In some embodiments, the method of treats a disorder or disease in whichaberrant Wnt signaling is implicated in a patient, the method comprisesadministering to the patient a therapeutically effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the disorder or disease is cancer.

In some embodiments, the disorder or disease is diabetic retinopathy.

In some embodiments, the disorder or disease is pulmonary fibrosis.

In some embodiments, the disorder or disease is rheumatoid arthritis.

In some embodiments, the disorder or disease is scleroderma.

In some embodiments, the disorder or disease is a mycotic or viralinfection.

In some embodiments, the disorder or disease is a bone or cartilagedisease.

In some embodiments, the disorder or disease is osteoarthritis.

In some embodiments, the disorder or disease is lung disease.

In some embodiments, the disorder or disease is a genetic disease causedby mutations in Wnt signaling components, wherein the genetic disease isselected from: polyposis coli, osteoporosis-pseudoglioma syndrome,familial exudative vitreoretinopathy, retinal angiogenesis, earlycoronary disease, tetra-amelia syndrome, Müllerian-duct regression andvirilization, SERKAL syndrome, diabetes mellitus type 2, Fuhrmannsyndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletaldysplasia, focal dermal hypoplasia, autosomal recessive anonychia,neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile Xsyndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome,Beckwith-Wiedemann Syndrome, Norrie disease and Rett syndrome.

In some embodiments, the patient is a human.

In some embodiments, the cancer is chosen from: hepatocellularcarcinoma, colon cancer, breast cancer, pancreatic cancer, chronicmyeloid leukemia (CML), chronic myelomonocytic leukemia, chroniclymphocytic leukemia (CLL), acute myeloid leukemia, acute lymphocyticleukemia, Hodgkin lymphoma, lymphoma, sarcoma and ovarian cancer.

In some embodiments, the cancer is chosen from: lung cancer—non-smallcell, lung cancer—small cell, multiple myeloma, nasopharyngeal cancer,neuroblastoma, osteosarcoma, penile cancer, pituitary tumors, prostatecancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skincancer—basal and squamous cell, skin cancer—melanoma, small intestinecancer, stomach cancers, testicular cancer, thymus cancer, thyroidcancer, uterine sarcoma, vaginal cancer, vulvar cancer, laryngeal orhypopharyngeal cancer, kidney cancer, Kaposi sarcoma, gestationaltrophoblastic disease, gastrointestinal stromal tumor, gastrointestinalcarcinoid tumor, gallbladder cancer, eye cancer (melanoma and lymphoma),Ewing tumor, esophagus cancer, endometrial cancer, colorectal cancer,cervical cancer, brain or spinal cord tumor, bone metastasis, bonecancer, bladder cancer, bile duct cancer, anal cancer and adrenalcortical cancer.

In some embodiments, the cancer is hepatocellular carcinoma.

In some embodiments, the cancer is colon cancer.

In some embodiments, the cancer is breast cancer.

In some embodiments, the cancer is pancreatic cancer.

In some embodiments, the cancer is chronic myeloid leukemia (CML).

In some embodiments, the cancer is chronic myelomonocytic leukemia.

In some embodiments, the cancer is chronic lymphocytic leukemia (CLL).

In some embodiments, the cancer is acute myeloid leukemia.

In some embodiments, the cancer is acute lymphocytic leukemia.

In some embodiments, the cancer is Hodgkin lymphoma.

In some embodiments, the cancer is lymphoma.

In some embodiments, the cancer is sarcoma.

In some embodiments, the cancer is ovarian cancer.

In some embodiments, the cancer is lung cancer—non-small cell.

In some embodiments, the cancer is lung cancer—small cell.

In some embodiments, the cancer is multiple myeloma.

In some embodiments, the cancer is nasopharyngeal cancer.

In some embodiments, the cancer is neuroblastoma.

In some embodiments, the cancer is osteosarcoma.

In some embodiments, the cancer is penile cancer.

In some embodiments, the cancer is pituitary tumors.

In some embodiments, the cancer is prostate cancer.

In some embodiments, the cancer is retinoblastoma.

In some embodiments, the cancer is rhabdomyosarcoma.

In some embodiments, the cancer is salivary gland cancer.

In some embodiments, the cancer is skin cancer—basal and squamous cell.

In some embodiments, the cancer is skin cancer—melanoma.

In some embodiments, the cancer is small intestine cancer.

In some embodiments, the cancer is stomach cancers.

In some embodiments, the cancer is testicular cancer.

In some embodiments, the cancer is thymus cancer.

In some embodiments, the cancer is thyroid cancer.

In some embodiments, the cancer is uterine sarcoma.

In some embodiments, the cancer is vaginal cancer.

In some embodiments, the cancer is vulvar cancer.

In some embodiments, the cancer is Wilms tumor.

In some embodiments, the cancer is laryngeal or hypopharyngeal cancer.

In some embodiments, the cancer is kidney cancer.

In some embodiments, the cancer is Kaposi sarcoma.

In some embodiments, the cancer is gestational trophoblastic disease.

In some embodiments, the cancer is gastrointestinal stromal tumor.

In some embodiments, the cancer is gastrointestinal carcinoid tumor.

In some embodiments, the cancer is gallbladder cancer.

In some embodiments, the cancer is eye cancer (melanoma and lymphoma).

In some embodiments, the cancer is Ewing tumor.

In some embodiments, the cancer is esophagus cancer.

In some embodiments, the cancer is endometrial cancer.

In some embodiments, the cancer is colorectal cancer.

In some embodiments, the cancer is cervical cancer.

In some embodiments, the cancer is brain or spinal cord tumor.

In some embodiments, the cancer is bone metastasis.

In some embodiments, the cancer is bone cancer.

In some embodiments, the cancer is bladder cancer.

In some embodiments, the cancer is bile duct cancer.

In some embodiments, the cancer is anal cancer.

In some embodiments, the cancer is adrenal cortical cancer.

In some embodiments, the disorder or disease is a neurologicalcondition, disorder or disease, wherein the neurologicalcondition/disorder/disease is selected from: Alzheimer's disease,frontotemporal dementias, dementia with lewy bodies, prion diseases,Parkinson's disease, Huntington's disease, progressive supranuclearpalsy, corticobasal degeneration, multiple system atrophy, amyotrophiclateral sclerosis (ALS), inclusion body myositis, autism, degenerativemyopathies, diabetic neuropathy, other metabolic neuropathies, endocrineneuropathies, orthostatic hypotension, multiple sclerosis andCharcot-Marie-Tooth disease.

In some embodiments, the compound of Formula (I) inhibits one or moreproteins in the Wnt pathway.

In some embodiments, the compound of Formula (I) inhibits signalinginduced by one or more Wnt proteins.

In some embodiments, the Wnt proteins are chosen from: WNT1, WNT2,WNT2B, WNT3, WNT3A, WNT4. WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A,WNT8B, WNT9A, WNT9B, WNT10A, WNT10B, WNT11, and WNT16.

In some embodiments, the compound of Formula (I) inhibits a kinaseactivity.

In some embodiments, the method of treats a disease or disorder mediatedby the Wnt pathway in a patient, the method comprises administering tothe patient a therapeutically effective amount of a compound (orcompounds) of Formula (I), or a pharmaceutically acceptable saltthereof.

In some embodiments, the compound of Formula (I) inhibits one or moreWnt proteins.

In some embodiments, the method of treats a disease or disorder mediatedby kinase activity in a patient, the method comprises administering tothe patient a therapeutically effective amount of a compound (orcompounds) of Formula (I), or a pharmaceutically acceptable saltthereof.

In some embodiments, the disease or disorder comprises tumor growth,cell proliferation, or angiogenesis.

In some embodiments, the method of inhibits the activity of a proteinkinase receptor, the method comprises contacting the receptor with aneffective amount of a compound (or compounds) of Formula (I), or apharmaceutically acceptable salt thereof.

In some embodiments, the method treats a disease or disorder associatedwith aberrant cellular proliferation in a patient; the method comprisesadministering to the patient a therapeutically effective amount of acompound (or compounds) of Formula (I), or a pharmaceutically acceptablesalt thereof.

In some embodiments, the method prevents or reduces angiogenesis in apatient; the method comprises administering to the patient atherapeutically effective amount of a compound (or compounds) of Formula(I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the method prevents or reduces abnormal cellularproliferation in a patient; the method comprises administering to thepatient a therapeutically effective amount of a compound (or compounds)of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the method of treats a disease or disorderassociated with aberrant cellular proliferation in a patient, the methodcomprising administering to the patient a pharmaceutical compositioncomprising one or more of the compounds of claim 1 in combination with apharmaceutically acceptable carrier and one or more other agents.

Moreover, the compounds and compositions, for example, as inhibitors ofthe CDKs, can modulate the level of cellular RNA and DNA synthesis andtherefore are expected to be useful in the treatment of viral infectionssuch as HIV, human papilloma virus, herpes virus, Epstein-Barr virus,adenovirus, Sindbis virus, pox virus and the like.

Compounds and compositions described herein can inhibit the kinaseactivity of, for example, CDK/cyclin complexes, such as those active inthe G_(0.) or G_(.1) stage of the cell cycle, e.g., CDK2, CDK4, and/orCDK6 complexes.

Evaluation of Biological Activity

The biological activity of the compounds described herein can be testedusing any suitable assay known to those of skill in the art, e.g., WO2001/053268 or WO 2005/009997. For example, the activity of a compoundmay be tested using one or more of the test methods outlined below.

In one example, tumor cells may be screened for Wnt independent growth.In such a method, tumor cells of interest are contacted with a compound(i.e. inhibitor) of interest, and the proliferation of the cells, e.g.by uptake of tritiated thymidine, is monitored. In some embodiments,tumor cells may be isolated from a candidate patient who has beenscreened for the presence of a cancer that is associated with a mutationin the Wnt signaling pathway. Candidate cancers include, withoutlimitation, those listed above.

In another example, one may utilize in vitro assays for Wnt biologicalactivity, e.g. stabilization of β-catenin and promoting growth of stemcells. Assays for biological activity of Wnt include stabilization ofβ-catenin, which can be measured, for example, by serial dilutions of acandidate inhibitor composition. An exemplary assay for Wnt biologicalactivity contacts a Wnt composition in the presence of a candidateinhibitor with cells, e.g. mouse L cells. The cells are cultured for aperiod of time sufficient to stabilize β-catenin, usually at least about1 hour, and lysed. The cell lysate is resolved by SDS PAGE, thentransferred to nitrocellulose and probed with antibodies specific forβ-catenin.

In a further example, the activity of a candidate compound can bemeasured in a Xenopus secondary axis bioassay (Leyns, L. et al. Cell(1997), 88(6), 747-756).

Example 7

Another screening assay for Wnt activity is described as follows.Reporter cell lines can be generated by stably transducing cells ofcancer cell lines (e.g., colon cancer) with a lentiviral construct thatinclude a wnt-responsive promoter driving expression of the fireflyluciferase gene.

Lentiviral constructs can be made in which the SP5 promoter, a promoterhaving eight TCF/LEF binding sites derived from the SP5 promoter, islinked upstream of the firefly luciferase gene. The lentiviralconstructs can also include a hygromycin resistance gene as a selectablemarker. The SP5 promoter construct can be used to transduce SW480 cells,a colon cancer cell line having a mutated APC gene that generates atruncated APC protein, leading to de-regulated accumulation ofβ-catenin. A control cell line can be generated using another lentiviralconstruct containing the luciferase gene under the control of the SV40promoter which does not require β-catenin for activation.

Cultured SW480 cells bearing a reporter construct can be distributed atapproximately 10,000 cells per well into 96 well or 384 well plates.Compounds from a small molecule compound library can then be added tothe wells in half-log dilutions using a ten micromolar topconcentration. A series of control wells for each cell type receive onlybuffer and compound solvent. Twenty-four to forty hours after theaddition of compound, reporter activity for luciferase can be assayed,for example, by addition of the BrightGlo luminescence reagent (Promega)and the Victor3 plate reader (Perkin Elmer). Readings can be normalizedto DMSO only treated cells, and normalized activities can then be usedin the IC₅₀ calculations. Table 2 shows the activity of selectedindazole-3-carboxamide analogs.

TABLE 2 Compound Wnt inhibition Compound Wnt inhibition 1   175 nM 2 5,000 nM 3   200 nM 4   160 nM 5 10,000 nM 6   270 nM 7   110 nM 8  130 nM 9 10,000 nM 11 10,000 nM 12    63 nM 13  1,250 nM 14   106 nM15    37 nM 16 10,000 nM 18   122 nM 19   107 nM 20   118 nM 23   120 nM26   210 nM 32  1,250 nM 36   275 nM 37  1,120 nM 38   120 nM 39    65nM 40    65 nM 41    67 nM 42   500 nM 43    63 nM 44   158 nM 45   110nM 46    15 nM 47    71 nM 48 10,000 nM 49    57 nM 50    71 nM 51    26nM 52    57 nM 53    63 nM 54   158 nM 55    44 nM 56   160 nM 57 10,000nM 58    71 nM 59  3,100 nM 60 10,000 nM 61   239 nM 62    16 nM 63  100 nM 64    6 nM 65   101 nM 66 10,000 nM 67 10,000 nM 68    48 nM 69   50 nM 70    41 nM 71    25 nM 72   215 nM 73   322 nM 74    65 nM 75   40 nM 76   850 nM 77  2,650 nM 78   239 nM 79   123 nM 80   158 nM 81  77-142 nM 82 143-188 nM 83 2,500-3,400 nM 84 822-898 nM 86    66 nM 87 2,440 nM 106    33 nM 124    67 nM 126    22 nM 162   426 nM 163 15,400nM 168    66 nM 169    49 nM 170    43 nM 172    60 nM 173    36 nM 174   48 nM 175    25 nM 176    30 nM 177   183 nM 178   297 nM 179    30nM 180    13 nM 181    38 nM 182    35 nM 183    49 nM 184    40 nM 185   27 nM 186   460 nM 187   215 nM 188    9 nM 189    85 nM 190  1,200nM

The term “comprising” as used herein is synonymous with “including,”“containing,” or “characterized by,” and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps.

What is claimed is:
 1. A compound which is

or a pharmaceutically acceptable salt thereof.
 2. A pharmaceuticalcomposition comprising a compound which is

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.